Bio


Dr. Rezvani is an Associate Professor of Medicine in the Division of Blood & Marrow Transplantation and Cell Therapy. He serves as the medical director of the inpatient BMT/cell therapy units at Stanford University and as Associate Clinical Chief of the Division. As a clinician, he cares for people undergoing allogeneic and autologous hematopoietic cell transplantation and other forms of cellular therapy. His research interests include optimizing the use of alternative donors for people who lack traditional fully-matched donors; the prevention and treatment of graft-vs.-host disease; the role of the microbiome in hematopoietic cell transplantation; and quality-of-care and systems improvement. He also teaches and serves as a research mentor for trainees in the Division of Blood & Marrow Transplant at Stanford.

Clinical Focus


  • Cancer > Blood and Marrow Transplant
  • Medical Oncology
  • CAR T Cell Therapy

Academic Appointments


Administrative Appointments


  • Associate Clinical Chief, Stanford University, Division of Blood & Marrow Transplantation (2020 - Present)
  • Inpatient Medical Director, Blood & Marrow Transplant Unit, Stanford University (2017 - Present)
  • Quality & Safety Director, Division of Blood & Marrow Transplantation (2021 - Present)
  • Cord Blood and Unrelated-Donor Director, Stanford University, Division of Blood & Marrow Transplantation (2018 - Present)

Honors & Awards


  • Member, Alpha Omega Alpha medical honor society (2001)

Boards, Advisory Committees, Professional Organizations


  • Member, Cord Blood Advisory Group, National Marrow Donor Program (2019 - Present)
  • Member, Protocol Development Committee, Protocol 1703, Blood & Marrow Transplant Clinical Trials Network (BMT-CTN) (2017 - Present)
  • Member, Conflict of Interest Committee, Blood & Marrow Transplant Clinical Trials Network (BMT-CTN) (2018 - Present)
  • Member, Toxicity and Supportive Care Committee, Blood & Marrow Transplant Clinical Trials Network (BMT-CTN) (2015 - 2018)
  • Editorial consultant, American College of Physicians PIER (2008 - 2016)

Professional Education


  • Board Certification: American Board of Internal Medicine, Medical Oncology (2021)
  • Fellowship, Fred Hutchinson Cancer Research Center/University of Washington, Medical Oncology (2008)
  • Residency, Duke University Medical Center, Internal Medicine (2004)
  • M.D., Temple University, Medicine (2001)
  • B.A., Stanford University, Slavic Languages and Literature (1997)

Current Research and Scholarly Interests


Clinical research in allogeneic hematopoietic cell transplantation

Clinical Trials


  • Autologous CD22 CAR T Cells in Adults w/ Recurrent or Refractory B Cell Malignancies Recruiting

    The primary purpose of this study is to test whether CD22-CAR T cells can be successfully made from immune cells collected from adults with relapsed/refractory B-cell malignancies (leukemia and lymphoma).

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  • Bone Marrow Grafting for Leukemia and Lymphoma Recruiting

    The purpose of this study is to obtain tissue samples for ongoing studies regarding transplant outcomes and complications.

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  • CD19/CD22 Chimeric Antigen Receptor (CAR) T Cells With or Without NKTR-255 in Adults With Recurrent or Refractory B Cell Malignancies Recruiting

    This phase I trial studies the side effects of CD19/CD22 chimeric antigen receptor (CAR) T cells when given together with chemotherapy and NKTR-255, and to see how well they work in treating patients with CD19 positive B acute lymphoblastic leukemia that has come back or does not respond to treatment. A CAR is a genetically-engineered receptor made so that immune cells (T cells) can attack cancer cells by recognizing and responding to the CD19/CD22 proteins. These proteins are commonly found on diffuse large B-cell lymphoma and B acute lymphoblastic leukemia. Drugs used in chemotherapy, such as cyclophosphamide and fludarabine phosphate, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. NKTR-255 is an investigational IL-15 receptor agonist designed to boost the immune system's natural ability to fight cancer. Giving CD19/CD22-CAR T cells and chemotherapy in combination with NKTR-255 may work better in treating patients with diffuse large B-cell lymphoma or B acute lymphoblastic leukemia.

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  • CD8+ Memory T-Cells as Consolidative Therapy After Donor Non-myeloablative Hematopoietic Cell Transplant in Treating Patients With Leukemia or Lymphoma Recruiting

    This phase 2 trial studies how well cluster of differentiation 8 (CD8)+ memory T-cells work as a consolidative therapy following a donor non-myeloablative hematopoietic cell transplant in treating patients with leukemia or lymphoma. Giving total lymphoid irradiation and anti-thymocyte globulin before a donor hematopoietic cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Giving cyclosporine and mycophenolate mofetil after the transplant may stop this from happening. Once the donated stem cells begin working, the patient's immune system may see the remaining cancer cells as not belonging in the patient's body and destroy them. Giving an infusion of the donor's white blood cells, such as CD8+ memory T-cells, may boost this effect and may be an effective treatment to kill any cancer cells that may be left in the body (consolidative therapy).

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  • Expanded Access of Omidubicel, for Allogeneic Transplantation in Patients With Hematological Malignancies Recruiting

    Omidubicel is an investigational therapy for patients with high-risk hematologic malignancies.

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  • Ibrutinib in Treating Patients With Refractory or Relapsed Lymphoma After Donor Stem Cell Transplant Recruiting

    This phase II trial studies how well ibrutinib works in treating patients after a donor stem cell transplant for lymphoma that is not responding to treatment or has come back. Ibrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

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  • MAGE A10ᶜ⁷⁹⁶T for Advanced NSCLC Recruiting

    This first time in human study is intended for men and women at least 18 years of age who have advanced lung cancer which has grown or returned after being treated. In particular, it is a study for subjects who have a blood test positive for HLA-A*02:01 and/or HLA-A*02:06 and a tumor test positive for MAGE A10 protein expression (protein or gene). This trial is a dose escalation trial that will evaluate 3 doses of transduced cells administered after a lymphodepleting chemotherapy regimen using a 3+3 dose escalation design .The study will take the subject's T cells, which are a natural type of immune cell in the blood, and send them to a laboratory to be modified. The changed T cells used in this study will be the subject's own T cells that have been genetically changed with the aim of attacking and destroying cancer cells. When the MAGE A10ᶜ⁷⁹⁶T cells are available, subjects will receive lymphodepleting chemotherapy with cyclophosphamide and fludarabine, followed by the T cell infusion. The purpose of this study is to test the safety of genetically changed T cells and find out what effects, if any, they have in subjects with lung cancer. The study will evaluate three different cell dose levels in order to find out the target cell dose. Once the target cell dose is determined, additional subjects will be enrolled to further test the safety and effects at this cell dose. Subjects will be seen frequently by the Study Physician right after receiving their T cells back and up to first 6 months. After that, subjects will be seen every three months. Subjects will be seen every 6 months by their Study Physician for the first 5 years after the T cell infusion. If the T cells are found in the blood at five years, then the subjects will continue to be seen once a year until the T cells are no longer found in the blood for a maximum of 15 years. If the T cells are no longer found in the blood at 5 years, then the subject will be contacted by the Study Physician for the next 10 years. Subjects who have a confirmed response or clinical benefit ≥4 weeks after the first T-cell infusion and whose tumor continues to express the appropriate antigen target may be eligible for a second infusion. All subjects, completing or withdrawing from the Interventional Phase of the study, will enter a 15-year long-term follow-up phase for observation of delayed adverse events. All subjects will continue to be followed for overall survival during the long-term follow-up phase.

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  • Obinutuzumab in cGVHD After Allogeneic Peripheral Blood Stem Cell Transplantation Recruiting

    This research study is studying a drug called obinutuzumab as a means of preventing chronic Graft vs. Host Disease (cGVHD).

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  • Safety Study of Cord Blood Units for Stem Cell Transplants Recruiting

    Background: - Cord blood is blood that is taken from the umbilical cord and placenta of healthy newborns after childbirth. The cord blood collected from a baby is called a cord blood unit. Cord blood units are stored frozen in public cord blood banks. About 10,000 cord blood transplants have been performed in children and adults for blood cancers and other diseases in the world. These transplants have helped save lives and improve treatments. However, not all available units of cord blood have been collected, stored, and licensed according to specific government requirements. These unlicensed units can still be used in transplant, but they can only be given as part of specific research studies. This study will evaluate the safety of giving these unlicensed units by recording any problems that may occur during and after giving the cord blood. Objectives: - To test the safety and effectiveness of unlicensed cord blood units in people who need stem cell transplants. Eligibility: - Individuals who are scheduled to have a stem cell transplant. Design: - Participants will be screened with a medical history and physical exam. - Participants will receive the cord blood unit as part of their stem cell transplant procedure. The transplant will be performed according to the current standard of care for the procedure. - After the transplant, participants will be monitored for up to 1 year. Any problems or side effects from the transplant will be treated as necessary. All outcomes will be reported to the National Cord Blood Program and to the Center for International Blood and Marrow Transplant.

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  • Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients With Relapsed or Refractory Germ Cell Tumors Recruiting

    This randomized phase III trial studies how well standard-dose combination chemotherapy works compared to high-dose combination chemotherapy and stem cell transplant in treating patients with germ cell tumors that have returned after a period of improvement or did not respond to treatment. Drugs used in chemotherapy, such as paclitaxel, ifosfamide, cisplatin, carboplatin, and etoposide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a stem cell transplant stops the growth of cancer cells by stopping them from dividing or killing them. Giving colony-stimulating factors, such as filgrastim or pegfilgrastim, and certain chemotherapy drugs, helps stem cells move from the bone marrow to the blood so they can be collected and stored. Chemotherapy is then given to prepare the bone marrow for the stem cell transplant. The stem cells are then returned to the patient to replace the blood-forming cells that were destroyed by the chemotherapy. It is not yet known whether high-dose combination chemotherapy and stem cell transplant are more effective than standard-dose combination chemotherapy in treating patients with refractory or relapsed germ cell tumors.

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  • A Multicenter Access and Distribution Protocol for Unlicensed Cryopreserved Cord Blood Units (CBUs) Not Recruiting

    This study is an access and distribution protocol for unlicensed cryopreserved cord blood units (CBUs) in pediatric and adult patients with hematologic malignancies and other indications.

    Stanford is currently not accepting patients for this trial.

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  • A Study of Ruxolitinib in Combination With Corticosteroids for the Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease (REACH-1) Not Recruiting

    The purpose of this study was to assess the efficacy of ruxolitinib in combination with corticosteroids in subjects with Grades II to IV steroid-refractory acute graft-versus-host disease (GVHD).

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • A Trial of the FMS-like Tyrosine Kinase 3 (FLT3) Inhibitor Gilteritinib Administered as Maintenance Therapy Following Allogeneic Transplant for Patients With FLT3/Internal Tandem Duplication (ITD) Acute Myeloid Leukemia (AML) Not Recruiting

    The purpose of this study is to compare relapse-free survival between participants with FLT3/ITD AML in first morphologic complete remission (CR1) who undergo hematopoietic stem cell transplant (HCT) and are randomized to receive gilteritinib or placebo beginning after the time of engraftment for a two year period.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • Aromatherapy for HSCT Distress Not Recruiting

    The purpose of this research is to evaluate aromatherapy inhaler use and how it may impact cancer distress and coping by patients in the first few days after hematopoietic stem cell transplant (HSCT).

    Stanford is currently not accepting patients for this trial.

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  • Axicabtagene Ciloleucel Expanded Access Study Not Recruiting

    A multicenter, open-label expanded access protocol for the treatment of subjects with relapsed/refractory large B-cell lymphoma.

    Stanford is currently not accepting patients for this trial.

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  • Donor Atorvastatin Treatment for Preventing Severe Acute Graft-Versus-Host Disease in Patients Undergoing Myeloablative Peripheral Blood Stem Cell Transplantation Not Recruiting

    This phase II trial studies donor atorvastatin treatment for the prevention of severe acute graft-versus-host disease (GVHD) in patients undergoing myeloablative peripheral blood stem cell (PBSC) transplantation. Giving chemotherapy and total-body irradiation (TBI) before a donor PBSC transplant helps stop the growth of cancer cells. It may also prevent the patient's immune system reject the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving atorvastatin to the donor before transplant may prevent this from happening.

    Stanford is currently not accepting patients for this trial. For more information, please contact Leah Galvez, 650-725-7951.

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  • Donor Regulatory T Cells in Treating Patients With Visceral Acute Graft-versus-Host Disease After Stem Cell Transplant Not Recruiting

    This phase I trial studies the side effects and best dose of donor regulatory T cells in treating patients with graft-versus-host disease affecting the liver or gastrointestinal organs (visceral) within 100 days (acute) after undergoing a stem cell transplant. Graft-versus-host disease occurs when donor immune cells infused in a stem cell transplant attack the gut, skin, liver, or other organ systems of the patient. Regulatory T cells are a type of immune cell that may be able to reduce the attack of the donor's immune cells on the patient's normal cells and help treat graft-vs-host disease.

    Stanford is currently not accepting patients for this trial. For more information, please contact Joanne Otani, 650-721-2372.

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  • Donor Umbilical Cord Blood Transplant With or Without Ex-vivo Expanded Cord Blood Progenitor Cells in Treating Patients With Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, or Myelodysplastic Syndromes Not Recruiting

    This randomized phase II trial studies how well donor umbilical cord blood transplant with or without ex-vivo expanded cord blood progenitor cells works in treating patients with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, or myelodysplastic syndromes. Giving chemotherapy and total-body irradiation before a donor umbilical cord blood transplant helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's cells. When the healthy stem cells and ex-vivo expanded cord blood progenitor cells are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. It is not yet known whether giving donor umbilical cord blood transplant plus ex-vivo expanded cord blood progenitor cells is more effective than giving a donor umbilical cord blood transplant alone.

    Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.

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  • Double Cord Versus Haploidentical (BMT CTN 1101) Not Recruiting

    Hematopoietic cell transplants (HCT)are one treatment option for people with leukemia or lymphoma. Family members,unrelated donors or banked umbilical cordblood units with similar tissue type can be used for HCT. This study will compare the effectiveness of two new types of bone marrow transplants in people with leukemia or lymphoma: one that uses bone marrow donated from family members with only partially matched bone marrow; and, one that uses two partially matched cord blood units.

    Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.

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  • Efficacy of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma Not Recruiting

    The purpose of this study is to evaluate whether axicabtagene ciloleucel therapy improves the clinical outcome compared with standard of care second-line therapy in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • Expanded Access Protocol for Tabelecleucel for Patients With Epstein-Barr Virus-Associated Viremia or Malignancies Not Recruiting

    The primary objective of this protocol is to provide expanded access to tabelecleucel to participants with Epstein-Barr virus-associated diseases and malignancies for whom there are no other appropriate therapeutic options, and who are not eligible to enroll in clinical studies designed to support the development and registration of tabelecleucel.

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • Fructooligosaccharides in Treating Patients With Blood Cancer Undergoing Donor Stem Cell Transplant Not Recruiting

    This pilot phase I trial studies the side effects and best dose of fructooligosaccharides in treating patients with blood cancer who are undergoing donor stem cell transplant. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells (called graft-versus-host disease). Nutritional supplements such as fructooligosaccharides may reduce the incidence of graft-versus-host disease in patients with blood cancer undergoing donor stem cell transplant.

    Stanford is currently not accepting patients for this trial. For more information, please contact Courtney Greene, 650-723-0387.

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  • Ibrutinib in Preventing Acute Leukemia in Patients After Reduced-Intensity Conditioning and Stem Cell Transplant Not Recruiting

    This phase II trial studies how well ibrutinib works in preventing acute leukemia in patients after reduced-intensity conditioning and stem cell transplant. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

    Stanford is currently not accepting patients for this trial. For more information, please contact Courtney Greene, 650-723-0387.

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  • Novel Approaches for Graft-versus-Host Disease Prevention Compared to Contemporary Controls (BMT CTN 1203) Not Recruiting

    Acute Graft-versus-Host-Disease (GVHD) is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). This study aims to determine if any of three new GVHD prophylaxis approaches improves the rate of GVHD and relapse free survival at one year after transplant compared to the current standard prophylaxis regimen.

    Stanford is currently not accepting patients for this trial. For more information, please contact Physician Referrals, 650-723-0822.

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  • Safety and Efficacy of KTE-C19 in Combination With Atezolizumab in Adults With Refractory Diffuse Large B-Cell Lymphoma (DLBCL) Not Recruiting

    The primary objective of phase 1 is to evaluate the safety of KTE-C19 and atezolizumab combination regimens. The primary objective of phase 2 is to evaluate the efficacy of KTE-C19 and atezolizumab, as measured by complete response rate in participants with refractory diffuse large B-cell lymphoma (DLBCL). Subjects who received an infusion of KTE-C19 will complete the remainder of the 15 year follow-up assessments in a separate long-term follow-up study, KT-US-982-5968

    Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.

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  • Stem Cell Transplantation With NiCord® (Omidubicel) vs Standard Umbilical Cord Blood in Patients With Leukemia, Lymphoma, and Myelodysplastic Syndrome (MDS) Not Recruiting

    This study is an open-label, controlled, multicenter, international, Phase III, randomized study of transplantation of NiCord® versus transplantation of one or two unmanipulated, unrelated cord blood units in patients with acute lymphoblastic leukemia or acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia or lymphoma, all with required disease features rendering them eligible for allogeneic transplantation.

    Stanford is currently not accepting patients for this trial. For more information, please contact Andrew Rezvani,, MD, 650-498-6000.

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  • Study of the Bruton's Tyrosine Kinase Inhibitor in Subjects With Chronic Graft Versus Host Disease Not Recruiting

    The purpose of this study is to assess the safety and clinical efficacy of ibrutinib in subjects with steroid dependent or refractory Chronic Graft Versus Host Disease.

    Stanford is currently not accepting patients for this trial. For more information, please contact Janet McDowell, 650-725-1647.

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  • TAC/MTX vs. TAC/MMF/PTCY for Prevention of Graft-versus-Host Disease and Microbiome and Immune Reconstitution Study (BMT CTN 1703/1801) Not Recruiting

    1703: The study is designed as a randomized, phase III, multicenter trial comparing two acute graft-versus-host disease (aGVHD) prophylaxis regimens: tacrolimus/methotrexate (Tac/MTX) versus post-transplant cyclophosphamide/tacrolimus/mycophenolate mofetil (PTCy/Tac/MMF) in the setting of reduced intensity conditioning (RIC) allogeneic peripheral blood stem cell (PBSC) transplantation. 1801: The goal of this protocol is to test the primary hypothesis that the engraftment stool microbiome diversity predicts one-year non-relapse mortality in patients undergoing reduced intensity allogeneic HCT.

    Stanford is currently not accepting patients for this trial. For more information, please contact Sivan Yani, 650-497-0330.

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All Publications


  • Impact of conditioning regimen intensity on the outcomes of peripheral T-cell lymphoma, anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma patients undergoing allogeneic transplant. British journal of haematology Savani, M., Ahn, K. W., Chen, Y., Ahmed, S., Cashen, A. F., Shadman, M., Modi, D., Khimani, F., Cutler, C. S., Zain, J., Brammer, J. E., Rezvani, A. R., Fenske, T. S., Sauter, C. S., Kharfan-Dabaja, M. A., Herrera, A. F., Hamadani, M. 1800

    Abstract

    There have been no large studies comparing reduced-intensity/non-myeloablative conditioning (RIC/NMA) to myeloablative conditioning (MAC) regimens in T-cell non-Hodgkin lymphoma (T-NHL) patients undergoing allogeneic transplant (allo-HCT). A total of 803 adults with peripheral T-cell lymphoma, anaplastic large cell lymphoma and angioimmunoblastic T-cell lymphoma (age 18-65years), undergoing allo-HCT between 2008-2019 and reported to the Center for International Blood and Marrow Transplant Research with either MAC (n=258) or RIC/NMA regimens (n=545) were evaluated. There were no significant differences between the two cohorts in terms of patient sex, race and performance scores. Significantly more patients in the RIC/NMA cohort had peripheral blood grafts, haematopoietic cell transplantation-specific comorbidity index (HCT-CI) of ≥3 and chemosensitive disease compared to the MAC cohort. On multivariate analysis, overall survival (OS) was not significantly different in the RIC/NMA cohort compared to the MAC cohort (hazard ratio (HR)=1.01, 95% confidence interval (CI)=0.79-1.29; p =0.95). Similarly, non-relapse mortality (NRM) (HR=0.85, 95% CI=0.61-1.19; p=0.34), risk of progression/relapse (HR=1.29; 95% CI=0.98-1.70; p =0.07) and therapy failure (HR=1.14; 95% CI=0.92-1.41, p=0.23) were not significantly different between the two cohorts. Relative to MAC, RIC/NMA was associated with a significantly lower risk of grade 3-4 acute graft-versus-host disease (HR=0.67; 95% CI=0.46-0.99, p=0.04). Among chemorefractory patients, there was no difference in OS, therapy failure, relapse, or NRM between RIC/NMA and MAC regimens. In conclusion, we found no association between conditioning intensity and outcomes after allo-HCT for T-cell NHL.

    View details for DOI 10.1111/bjh.18052

    View details for PubMedID 35106754

  • Rare transmission of commensal and pathogenic bacteria in the gut microbiome of hospitalized adults. Nature communications Siranosian, B. A., Brooks, E. F., Andermann, T., Rezvani, A. R., Banaei, N., Tang, H., Bhatt, A. S. 1800; 13 (1): 586

    Abstract

    Bacterial bloodstream infections are a major cause of morbidity and mortality among patients undergoing hematopoietic cell transplantation (HCT). Although previous research has demonstrated that pathogens may translocate from the gut microbiome into the bloodstream to cause infections, the mechanisms by which HCT patients acquire pathogens in their microbiome have not yet been described. Here, we use linked-read and short-read metagenomic sequencing to analyze 401 stool samples collected from 149 adults undergoing HCT and hospitalized in the same unit over three years, many of whom were roommates. We use metagenomic assembly and strain-specific comparison methods to search for high-identity bacterial strains, which may indicate transmission between the gut microbiomes of patients. Overall, the microbiomes of patients who share time and space in the hospital do not converge in taxonomic composition. However, we do observe six pairs of patients who harbor identical or nearly identical strains of the pathogen Enterococcus faecium, or the gut commensals Akkermansia muciniphila andHungatella hathewayi. These shared strains may result from direct transmission between patients who shared a room and bathroom, acquisition from a common hospital source, or transmission from an unsampled intermediate. We also identify multiple patients with identical strains of species commonly found in commercial probiotics, including Lactobacillus rhamnosus and Streptococcus thermophilus. In summary, our findings indicate that sharing of identical pathogens between the gut microbiomes of multiple patients is a rare phenomenon. Furthermore, the observed potential transmission of commensal, immunomodulatory microbes suggests that exposure to other humans may contribute to microbiome reassembly post-HCT.

    View details for DOI 10.1038/s41467-022-28048-7

    View details for PubMedID 35102136

  • Real-world Experience of Cryopreserved Allogeneic Hematopoietic Grafts in the COVID-19 Pandemic: A Single Center Report. Transplantation and cellular therapy Bankova, A. K., Caveney, J., Yao, B., Ramos, T. L., Bogeholz, J., Heydari, K., Diaz, N., Jackson, M. L., Lowsky, R., Brown, J. W., Johnston, L., Rezvani, A. R., Frank, M. J., Muffly, L., Weng, W., Sidana, S., Negrin, R. S., Miklos, D. B., Shiraz, P., Meyer, E. H., Shizuru, J. A., Arai, S. 1800

    Abstract

    BACKGROUND: As a result of the COVID-19 widespread pandemic, cryopreservation of allogeneic donor apheresis products was implemented to mitigate the challenges of donor availability and product transport. Although logistically beneficial, the impact of cryopreservation on clinical outcomes and graft composition remains unclear.OBJECTIVES: To compare the outcomes and graft composition with cryopreserved versus fresh allografts in the setting of allogeneic hematopoietic cell transplantation (allo-HCT).STUDY DESIGN: We retrospectively analyzed the clinical outcomes of 30 consecutive patients who received cryopreserved allografts between March and August 2020 as compared to 60 consecutive patients who received fresh allografts prior to the COVID-19 pandemic. Primary endpoints were hematopoietic engraftment, graft failure (GF) and secondary outcomes were overall survival (OS), relapse free survival (RFS) and non-relapse mortality (NRM). In addition, extended immunophenotype analysis was performed on cryopreserved versus prospectively collected fresh apheresis samples.RESULTS: Compared to fresh allografts, both neutrophil and platelet recovery were delayed in recipients of cryopreserved reduced intensity conditioning (RIC) allo-HCT with median times to engraftment of 24 days vs 18 days (P = .01) and 27 days vs 18 days (P = .069), respectively. We observed primary GF in 4 of 30 patients in the cryopreserved cohort (13.3%) vs only one of 60 patients (1.7 %) in the fresh cohort (P = .03). Cryopreserved RIC allo-HCT was associated with significantly lower median total, myeloid and T-cell donor chimerism at 1 month. OS and RFS were inferior for cryograft recipients with hazard ratio [HR (95%Cl)]: 2.16 (1.00, 4.67) and 1.90 (0.95, 3.79), respectively. Using an extended immunophenotype analysis we compared 14 samples from the cryopreserved cohort to 6 prospectively collected fresh apheresis donor samples. These analyses showed both decrease in total cell viability and significantly reduced absolute numbers of NK cells (CD3-CD56+) in the cryopreserved apheresis samples.CONCLUSION: In this single institution study we note delayed engraftment and a trend toward clinical inferiority of cryopreserved vs fresh allografts. Further evaluation of the use of cryopreserved allografts and their impact on clinical and laboratory outcomes is warranted.

    View details for DOI 10.1016/j.jtct.2022.01.010

    View details for PubMedID 35042013

  • Incidence and risk factors associated with bleeding and thrombosis following chimeric antigen receptor T-cell therapy BLOOD ADVANCES Johnsrud, A., Craig, J., Baird, J., Spiegel, J., Muffly, L., Zehnder, J., Tamaresis, J., Negrin, R., Johnston, L., Arai, S., Shizuru, J., Lowsky, R., Meyer, E., Weng, W., Shiraz, P., Rezvani, A., Latchford, T., Mackall, C., Miklos, D., Frank, M., Sidana, S. 2021; 5 (21): 4465-4475
  • Concordance of peripheral blood and bone marrow measurable residual disease in adult acute lymphoblastic leukemia. Blood advances Muffly, L., Sundaram, V., Chen, C., Yurkiewicz, I., Kuo, E., Burnash, S., Spiegel, J. Y., Arai, S., Frank, M. J., Johnston, L. J., Lowsky, R., Meyer, E. H., Negrin, R. S., Rezvani, A. R., Sidana, S., Shiraz, P., Shizuru, J. A., Weng, W., Liedtke, M., Vempaty, H. T., Miklos, D. B. 2021; 5 (16): 3147-3151

    Abstract

    Monitoring of measurable residual disease (MRD) is essential to the management of acute lymphoblastic leukemia (ALL) and is typically performed through repeated bone marrow (BM) assessments. Using a next-generation sequencing (NGS) MRD platform, we performed a prospective observational study evaluating the correlation between peripheral blood (PB) and BM MRD in adults with ALL receiving cellular therapies (hematopoietic cell transplantation [HCT] and chimeric antigen receptor T-cell [CAR-T] therapies). Among the study cohort (N = 69 patients; 126 paired PB/BM samples), we found strong correlation between PB and BM MRD (r = 0.87; P < .001), with a sensitivity and specificity of MRD detection in the PB of 87% and 90%, respectively, relative to MRD in the BM. MRD became detectable in the PB in 100% of patients who subsequently relapsed following HCT, with median time from MRD+ to clinical relapse of 90 days, and in 85% of patients who relapsed following CAR T, with median time from MRD+ to clinical relapse of 60 days. In adult patients with ALL undergoing cellular therapies, we demonstrate strong concordance between NGS-based MRD detected in the PB and BM. Monitoring of ALL MRD in the PB appears to be an adequate alternative to frequent invasive BM evaluations in this clinical setting.

    View details for DOI 10.1182/bloodadvances.2021004234

    View details for PubMedID 34424318

  • CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: a phase 1 trial. Nature medicine Spiegel, J. Y., Patel, S., Muffly, L., Hossain, N. M., Oak, J., Baird, J. H., Frank, M. J., Shiraz, P., Sahaf, B., Craig, J., Iglesias, M., Younes, S., Natkunam, Y., Ozawa, M. G., Yang, E., Tamaresis, J., Chinnasamy, H., Ehlinger, Z., Reynolds, W., Lynn, R., Rotiroti, M. C., Gkitsas, N., Arai, S., Johnston, L., Lowsky, R., Majzner, R. G., Meyer, E., Negrin, R. S., Rezvani, A. R., Sidana, S., Shizuru, J., Weng, W., Mullins, C., Jacob, A., Kirsch, I., Bazzano, M., Zhou, J., Mackay, S., Bornheimer, S. J., Schultz, L., Ramakrishna, S., Davis, K. L., Kong, K. A., Shah, N. N., Qin, H., Fry, T., Feldman, S., Mackall, C. L., Miklos, D. B. 2021

    Abstract

    Despite impressive progress, more than 50% of patients treated with CD19-targeting chimeric antigen receptor T cells (CAR19) experience progressive disease. Ten of 16 patients with large B cell lymphoma (LBCL) with progressive disease after CAR19 treatment had absent or low CD19. Lower surface CD19 density pretreatment was associated with progressive disease. To prevent relapse with CD19- or CD19lo disease, we tested a bispecific CAR targeting CD19 and/or CD22 (CD19-22.BB.z-CAR) in a phase I clinical trial ( NCT03233854 ) of adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and LBCL. The primary end points were manufacturing feasibility and safety with a secondary efficacy end point. Primary end points were met; 97% of products met protocol-specified dose and no dose-limiting toxicities occurred during dose escalation. In B-ALL (n=17), 100% of patients responded with 88% minimal residual disease-negative complete remission (CR); in LBCL (n=21), 62% of patients responded with 29% CR. Relapses were CD19-/lo in 50% (5 out of 10) of patients with B-ALL and 29% (4 out of 14) of patients with LBCL but were not associated with CD22-/lo disease. CD19/22-CAR products demonstrated reduced cytokine production when stimulated with CD22 versus CD19. Our results further implicate antigen loss as a major cause of CAR T cell resistance, highlight the challenge of engineering multi-specific CAR T cells with equivalent potency across targets and identify cytokine production as an important quality indicator for CAR T cell potency.

    View details for DOI 10.1038/s41591-021-01436-0

    View details for PubMedID 34312556

  • A fructo-oligosaccharide prebiotic is well-tolerated in adults undergoing allogeneic hematopoietic stem cell transplantation: a phase I dose-escalation trial. Transplantation and cellular therapy Andermann, T. M., Fouladi, F., Tamburini, F. B., Sahaf, B., Tkachenko, E., Greene, C., Buckley, M. T., Brooks, E. F., Hedlin, H., Arai, S., Mackall, C. L., Miklos, D., Negrin, R. S., Fodor, A. A., Rezvani, A. R., Bhatt, A. S. 2021

    Abstract

    BACKGROUND: Alterations of the gut microbiota after allogeneic hematopoietic cell transplantation (allo-HCT) are a key factor in the development of transplant-related complications such as graft-versus-host disease (GVHD). Interventions that preserve the gut microbiome hold promise to improve HCT-associated morbidity and mortality. Murine models demonstrate that prebiotics such as fructo-oligosaccharides (FOS) may increase gut levels of short-chain fatty acids (SCFAs) such as butyrate, and consequently induce proliferation of immunomodulatory FOXP3+ CD4+ T-regulatory cells (Tregs), that impact GVHD risk.METHODS: We conducted a pilot Phase I trial to assess the investigate the maximum tolerated dose of FOS in patients undergoing reduced-intensity (RIC) allo-HCT (n=15) compared to concurrent controls (n=16). We administered FOS starting at pretransplant conditioning and continuing for a total of 21 days. We characterized the gut microbiome using shotgun metagenomic sequencing, measured stool SCFAs using LC-MS, and determined peripheral T-cell concentrations using CyTOF.RESULTS: We found that FOS was safe and well-tolerated at 10g per day without significant adverse effects in patients undergoing allo-HCT. Community-level gut microbiota composition was significantly different on the day of transplant (day 0) between patients receiving FOS compared to concurrent controls, however FOS-associated alterations of the gut microbiota were not sustained after transplant. Although the impact of FOS was fleeting, transplantation itself impacted a substantial number of taxa over time. In our small pilot trial, no significant differences were observed in gut microbial metabolic pathways, stool SCFAs, or in peripheral Tregs although Tregs trended higher in those patients who received FOS. A marker of CD4+ T-cell activation, namely CTLA4+, was significantly higher in patients receiving FOS, whereas a non-significant trend existed for FOP3+CD4+ T-regulatory cells that were higher in those receiving FOS compared to controls.CONCLUSIONS: FOS is well-tolerated at 10g per day in patients undergoing RIC allo-HCT. While alterations in the gut microbiota and peripheral immune cell composition in those receiving FOS are intriguing, additional studies are required to investigate the use of prebiotics in HCT recipients.

    View details for DOI 10.1016/j.jtct.2021.07.009

    View details for PubMedID 34274493

  • Engraftment of double cord blood transplantation after non-myeloablative conditioning with escalated total body irradiation dosing to facilitate engraftment in immunocompetent patients. Transplantation and cellular therapy Brunstein, C. G., DeFor, T. E., Fuchs, E. J., Karanes, C., McGuirk, J. P., Rezvani, A. R., Eapen, M., O'Donnell, P. V., Weisdorf, D. J., Blood and Marrow Transplant Clinical Trials Network.,, 2021

    Abstract

    BACKGROUND: In order to improve accrual to a randomized clinical trial of double unrelated cord blood (dUCB) versus HLA-haploidentical bone marrow (Haplo-BM) transplantation, patients with less prior therapy and potentially greater immunocompetence were enrolled. In order to reduce the risk of graft rejection, patients randomized to receive dUCB received a higher dose of total body irradiation (TBI) (300 vs. 200 centiGray [cGy]).OBJECTIVE: Determine whether inclusion of recipients of 300 cGy TBI influenced the trial outcomes.STUDY DESIGN: This was a secondary analysis of dUCB recipients: 161 received TBI 200 cGy and 18 received TBI 300 cGy. Fine and Gray regression was used to evaluate the effect of TBI dose on relapse and non-relapse mortality (NRM). Cox regression was used for neutrophil engraftment and overall survival.RESULTS: Patient characteristics were similar in both TBI dose subgroups. The probability of neutrophil engraftment was 100% for patients who received TBI 300 cGy vs. 91% (95%CI, 86-95%) with TBI 200 cGy (p=0.64), which was similar after regression analysis adjusting for age, total infused nucleated cell dose, HLA matching to the patient, and comorbidity score. We also investigated whether the lower survival probability and higher cumulative incidence of NRM observed in the dUCB arm of BMT CTN 1101 could be influenced by the TBI 300 cGy patient subset. There was no significant difference in the 1-year incidences of NRM and relapse, nor in 1-year survival, even after adjusting in multivariate analysis.CONCLUSION: Patients in BMT CTN 1101 who received TBI 300 cGy and 200 cGy had similar engraftment and early mortality. We conclude that inclusion of a modified regimen for dUCB transplantation had no demonstrable influence on this large randomized trial.

    View details for DOI 10.1016/j.jtct.2021.07.006

    View details for PubMedID 34273598

  • Outcomes after delayed and second autologous stem cell transplant in patients with relapsed multiple myeloma. Bone marrow transplantation Lemieux, C., Muffly, L. S., Iberri, D. J., Craig, J. K., Johnston, L. J., Lowsky, R., Shiraz, P., Rezvani, A. R., Frank, M. J., Weng, W., Meyer, E., Shizuru, J. A., Arai, S., Liedtke, M., Negrin, R. S., Miklos, D. B., Sidana, S. 2021

    Abstract

    We evaluated the outcomes of 168 patients undergoing delayed or second autologous stem cell transplant (ASCT) for relapsed multiple myeloma (MM) from 2010 to 2019. Overall, 21% (n=35) patients had received a prior transplant and 69% (n=116) underwent transplant at first relapse. Overall, 27% patients had high-risk cytogenetics and 15% had ISS stage III disease. Stem cell collection was performed after relapse in 72% and 35% of patients received maintenance therapy. Median PFS from salvage treatment and transplant were 28 and 19 months, respectively. Median OS from salvage treatment and transplant was 69 and 55 months. Multivariate analysis revealed that ASCT in first relapse was associated with superior PFS (HR 0.63, p=0.03) and OS (HR 0.59, p=0.04) compared to later lines of therapy. In addition, PFS of ≥36 months with prior therapy was associated with improved PFS (HR 0.62, p=0.04) and OS (HR 0.41, p=0.01). Ninety-five patients underwent delayed transplant at first relapse, median PFS and OS from start of therapy was 30 and 69 months, and median OS from diagnosis was 106 months. These data may serve as a guide when counseling patients undergoing ASCT for relapsed MM and provide a benchmark in designing clinical trials of transplantation/comparative treatments for relapsed MM.

    View details for DOI 10.1038/s41409-021-01371-1

    View details for PubMedID 34163014

  • Omidubicel Versus Standard Myeloablative Umbilical Cord Blood Transplantation: Results of a Phase III Randomized Study. Blood Horwitz, M. E., Stiff, P. J., Cutler, C. S., Brunstein, C. G., Hanna, R., Maziarz, R. T., Rezvani, A. R., Karras, N. A., McGuirk, J. P., Valcarcel, D., Schiller, G. J., Lindemans, C. A., Hwang, W. Y., Koh, L., Keating, A. K., Khaled, Y., Hamerschlak, N., Frankfurt, O., Peled, T., Segalovich, I., Blackwell, B., Wease, S., Freedman, L. S., Galamidi-Cohen, E., Sanz, G. F. 2021

    Abstract

    Omidubicel is an ex vivo expanded hematopoietic progenitor cell, and non-expanded myeloid and lymphoid cell product derived from a single umbilical cord blood unit. We report results of a phase III trial to evaluate the efficacy of omidubicel compared to standard umbilical cord blood transplantation (UCBT). Between January 2017 and January 2020, 125 patients aged 13-65 with hematologic malignancies were randomized to omidubicel versus standard UCBT. Patients received myeloablative conditioning and graft versus host disease (GvHD) prophylaxis with a calcineurin inhibitor and mycophenolate mofetil. The primary endpoint was time to neutrophil engraftment. The treatment arms were well balanced and racially diverse. Median time to neutrophil engraftment was 12 days (95% CI 10-14 days) and 22 days (95% CI 19-25 days) (p<0.001) for the omidubicel and control arms, respectively. The cumulative incidence of neutrophil engraftment was 96% and 89% for patients receiving omidubicel and control transplants, respectively. The omidubicel arm had faster platelet recovery (55% vs. 35% recovery by 42 days, p=0.028), a lower incidence of first grade 2/3 bacterial or invasive fungal infections (37% vs. 57%, p=0.027), and spent more time out of hospital during the first 100 days following transplant (median 61 vs. 48 days, p=0.005) than controls. Differences in GvHD and survival between the two arms were not statistically significant. Transplantation with omidubicel results in faster hematopoietic recovery and reduced early transplant-related complications as compared to standard UCBT. The results suggest that omidubicel may be considered as a new standard of care for adult patients eligible for UCBT.

    View details for DOI 10.1182/blood.2021011719

    View details for PubMedID 34157093

  • Inferior Clinical Outcomes in Recipients of Cryopreserved Grafts Following Reduced Intensity Allogeneic Hematopoietic Cell Transplantation: A Single Center Report Bankova, A., Caveney, J., Ramos, T., Bogeholz, J., Heydari, K., Diaz, N., Jackson, M., Lowsky, R., Brown, J., Johnston, L., Rezvani, A., Frank, M., Muffly, L., Weng, W., Sidana, S., Negrin, R., Miklos, D., Shiraz, P., Meyer, E., Shizuru, J., Arai, S. SPRINGERNATURE. 2021: 181
  • Phase 2 study of MGTA-145+plerixafor for rapid and reliable hematopoietic stem cell (HSC) mobilization for autologous transplant in multiple myeloma. Sidana, S., Bankova, A., Hosoya, H., Muffly, L. S., Kumar, S., Johnston, L. J., Lowsky, R., Meyer, E., Rezvani, A., Weng, W., Arai, S., Frank, M., Shiraz, P., Howell, H., Goncalves, K. A., Schmelmer, V., Davis, J., Shizuru, J., Miklos, D. LIPPINCOTT WILLIAMS & WILKINS. 2021
  • Outcomes Associated With Thiotepa-Based Conditioning in Patients With Primary Central Nervous System Lymphoma After Autologous Hematopoietic Cell Transplant. JAMA oncology Scordo, M., Wang, T. P., Ahn, K. W., Chen, Y., Ahmed, S., Awan, F. T., Beitinjaneh, A., Chen, A., Chow, V. A., Dholaria, B., Epperla, N., Farooq, U., Ghosh, N., Grover, N., Hamad, N., Hildebrandt, G. C., Holmberg, L., Hong, S., Inwards, D. J., Jimenez-Jimenez, A., Karmali, R., Kenkre, V. P., Khimani, F., Klyuchnikov, E., Krem, M. M., Munshi, P. N., Nieto, Y., Prestidge, T., Ramakrishnan Geethakumari, P., Rezvani, A. R., Riedell, P. A., Seo, S., Shah, N. N., Solh, M., Yared, J. A., Kharfan-Dabaja, M. A., Herrera, A., Hamadani, M., Sauter, C. S. 2021

    Abstract

    Importance: Primary central nervous system lymphoma (PCNSL) requires induction and consolidation to achieve potential cure. High-dose therapy and autologous hematopoietic cell transplant (AHCT) is an accepted and effective consolidation strategy for PCNSL, but no consensus exists on the optimal conditioning regimens.Objective: To assess the outcomes in patients with PCNSL undergoing AHCT with the 3 most commonly used conditioning regimens: thiotepa/busulfan/cyclophosphamide (TBC), thiotepa/carmustine (TT-BCNU), and carmustine/etoposide/cytarabine/melphalan (BEAM).Design, Setting, and Participants: This observational cohort study used registry data from the Center for International Blood and Marrow Transplant Research registry. The Center is a working group of more than 380 transplantation centers worldwide that contributed detailed data on HCT to a statistical center at the Medical College of Wisconsin, Milwaukee. The participant data were from 603 adult patients with PCNSL who underwent AHCT as initial, or subsequent, consolidation between January 2010 and December 2018. Patients were excluded if they had a non-Hodgkin lymphoma subtype other than diffuse large B-cell lymphoma, systemic non-Hodgkin lymphoma, or HIV; received an uncommon conditioning regimen; or were not in partial remission or complete remission prior to AHCT. Statistical analysis was performed from July 5, 2020, to March 1, 2021.Interventions: Patients received 1 of 3 conditioning regimens: TBC (n=263), TT-BCNU (n=275), and BEAM (n=65).Main Outcomes and Measures: The primary outcome was progression-free survival. Secondary outcomes included hematopoietic recovery, incidence of relapse, nonrelapse mortality, and overall survival.Results: Of 603 patients, the mean age was 57 (range, 19-77) years and 318 (53%) were male. The 3-year adjusted progression-free survival rates were higher in the TBC cohort (75%) and TT-BCNU cohort (76%) compared with the BEAM cohort (58%) (P=.03) owing to a higher relapse risk in the BEAM cohort (hazard ratio [HR], 4.34; 95% CI, 2.45-7.70; P<.001). In a multivariable regression analysis, compared with the TBC cohort, patients who received TT-BCNU had a higher relapse risk (HR, 1.79; 95% CI, 1.07-2.98; P=.03), lower risk of nonrelapse mortality (NRM) (HR, 0.50; 95% CI, 0.29-0.87; P=.01), and similar risk of all-cause mortality more than 6 months after HCT (HR, 1.54; 95% CI, 0.93-2.55; P=.10). Age of 60 years or older, Karnofsky performance status less than 90, and an HCT-comorbidity index greater than or equal to 3 were associated with lower rates of survival across all 3 cohorts. Subgroup analyses demonstrated that patients aged 60 years and older had considerably higher NRM with TBC.Conclusions and Relevance: In this cohort study, thiotepa-based conditioning regimen was associated with higher rates of survival compared with BEAM, despite higher rates of early toxic effects and NRM; these findings may assist clinicians in choosing between TBC or TT-BCNU based on patient and disease characteristics.

    View details for DOI 10.1001/jamaoncol.2021.1074

    View details for PubMedID 33956047

  • Stem Cell Mobilization in Multiple Myeloma: Comparing Safety and Efficacy of Cyclophosphamide +/- Plerixafor vs. G-CSF +/- Plerixafor in the Lenalidomide Era. Transplantation and cellular therapy Johnsrud, A., Ladha, A., Muffly, L., Shiraz, P., Goldstein, G., Osgood, V., Shizuru, J. A., Johnston, L., Arai, S., Weng, W., Lowsky, R., Rezvani, A. R., Meyer, E. H., Frank, M. J., Negrin, R. S., Miklos, D. B., Sidana, S. 2021

    Abstract

    Growth factor and chemotherapy-based stem cell mobilization strategies are commonly used for patients with multiple myeloma. We retrospectively compared 398 patients mobilized between 2017-2020 using either cyclophosphamide (4g/m2) plus granulocyte colony stimulating factor (GCSF) or G-CSF alone, with on demand plerixafor (PXF) in both groups. While total CD34+yield was higher after chemo-mobilization compared to GCSF+/-PXF (median 13.6 vs. 4.4 * 106/kg,P< .01), achievement of≥2 * 106CD34+ cells (95% vs 93.7%,P= .61), and rates of mobilization failure (5% vs. 6.3%,P= .61) were similar. Fewer patients required PXF with chemo-mobilization (12.3% vs 49.5%,P< .01), and apheresis sessions were fewer (median: 1, range 1-4 vs. 2, range 1-5). Complications were higher after chemo-mobilization (30% vs. 7.4%,P< .01), including neutropenic fever, ED visits, and hospitalizations. Prior lenalidomide≤6 cycles did not impair cell yield in either group.Median cost of mobilization was 17.4% lower in the GCSF +/- PXF group (P= .01).Differences in time to engraftment were not clinically significant. Given similar rates mobilization success, engraftment time, and less toxicity and lower costs compared to chemo-mobilization, G-CSF with on-demand PXF may be preferable in myeloma patients with adequate disease control and limited lenalidomide exposure.

    View details for DOI 10.1016/j.jtct.2021.04.016

    View details for PubMedID 33915323

  • Guidelines for Adult Patient Selection and Conditioning Regimens in Cord Blood Transplant Recipients with Hematologic Malignancies and Aplastic Anemia. Transplantation and cellular therapy Metheny, L., Politikos, I., Ballen, K. K., Rezvani, A. R., Milano, F., Barker, J. N., Brunstein, C. G., American Society for Transplantation and Cellular Therapy Cord Blood Special Interest Group 2021; 27 (4): 286–91

    Abstract

    For cord blood transplantation (CBT), appropriate patient and conditioning regimen selection is necessary to achieve long-term disease-free survival. This review aims to provide comprehensive guidelines on these issues using evidence from the literature and experience at dedicated CBT centers. Topics include patient and disease characteristics that make CBT a good or poor choice and a review of outcomes in commonly used conditioning regimens in CBT. This is accompanied with recommendations on regimen intensity based on disease, organ function, and patient performance status and age. In addition, the use of antithymocyte globulin in CBT is discussed, as is the choice of conditioning in aplastic anemia patients who have access to acceptable CB units.

    View details for DOI 10.1016/j.jtct.2020.11.008

    View details for PubMedID 33836867

  • Use of Backup Stem Cells for Stem Cell Boost and Second Transplant in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation. Transplantation and cellular therapy Liang, E. C., Muffly, L. S., Shiraz, P., Shizuru, J. A., Johnston, L., Arai, S., Frank, M. J., Weng, W., Lowsky, R., Rezvani, A., Meyer, E. H., Negrin, R., Miklos, D. B., Sidana, S. 2021

    Abstract

    Autologous hematopoietic stem cell transplantation (ASCT) is a standard treatment for multiple myeloma (MM). Consensus guidelines recommend collecting sufficient stem cells in case there is a need for stem cell boost for delayed/poor engraftment or for future second ASCT. However, collecting and storing backup stem cells in all patients requires significant resources and cost, and the rates of backup stem cell utilization are not well studied. We sought to examine the utilization of backup stem cells (BSCs) in patients with MM undergoing ASCT. Patients with MM aged ≥18 years old who underwent first ASCT at our institution from January 2010 through December 2015 and collected sufficient stem cells for at least 2 transplants were included in this single-center retrospective study. This timeframe was selected to allow for adequate follow-up. A total of 393 patients were included. The median age was 58 years (range, 25-73). After a median follow-up of 6 years, the median progression-free survival (PFS) of the cohort was 3 years. Sixty-one percent (n=240) of patients progressed or relapsed. Chemotherapy-based mobilization was used in almost all patients (98%). The median total CD34+ cells collected was 18.2*106/kg (range, 3.4-112.4). A median of 5.7*106 CD34+ cells/kg (range, 1.8-41.9) was infused during the first ASCT, and a median of 10.1*106 CD34+ cells/kg (range, 1.5-104.5) was cryopreserved for future use. Of the patients, 6.9% (n=27) used backup stem cells, with 2.3% (n=10) using them for stem cell boost, 4.6% (n=18) for a second salvage ASCT, including 1 patient for both stem cell boost and second ASCT. Rates of backup stem cell use among patients aged <60, 60-69, and ≥70 years were 7.8%, 5.7%, and 5.9%, respectively. There was a trend toward higher rates of backup stem cell use for second ASCT in patients who were younger, had suboptimal disease control at time of first ASCT, and longer PFS. The median dose of stem cell boost given was 5.6*106 CD34+ cells/kg (range, 1.9-20). The median time from stem cell boost to neutrophil, hemoglobin, and platelet engraftment was 4 (range, 2-11), 15 (range, 4-34), and 12 (range, 0-34) days, respectively. Lower CD34+ dose and older age at time of ASCT predicted need for stem cell boost. With new salvage therapies for relapsed MM, the rates of second ASCT are very low. The low rates of use suggest that institutional policies regarding universal BSC collection and long-term storage should be reassessed and individualized. However, need for stem cell boost in 2.3% of patients may present a challenge to that.

    View details for DOI 10.1016/j.jtct.2021.02.026

    View details for PubMedID 33775587

  • Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial. Blood Fuchs, E. J., O'Donnell, P. V., Eapen, M., Logan, B., Antin, J. H., Dawson, P., Devine, S., Horowitz, M. M., Horwitz, M. E., Karanes, C., Leifer, E., Magenau, J. M., McGuirk, J. P., Morris, L. E., Rezvani, A. R., Jones, R. J., Brunstein, C. G. 2021; 137 (3): 420-428

    Abstract

    Results of 2 parallel phase 2 trials of transplantation of unrelated umbilical cord blood (UCB) or bone marrow (BM) from HLA-haploidentical relatives provided equipoise for direct comparison of these donor sources. Between June 2012 and June 2018, 368 patients aged 18 to 70 years with chemotherapy-sensitive lymphoma or acute leukemia in remission were randomly assigned to undergo UCB (n = 186) or haploidentical (n = 182) transplant. Reduced-intensity conditioning comprised total-body irradiation with cyclophosphamide and fludarabine for both donor types. Graft-versus-host disease prophylaxis for UCB transplantation was cyclosporine and mycophenolate mofetil (MMF) and for haploidentical transplantation, posttransplant cyclophosphamide, tacrolimus, and MMF. The primary end point was 2-year progression-free survival (PFS). Treatment groups had similar age, sex, self-reported ethnic origin, performance status, disease, and disease status at randomization. Two-year PFS was 35% (95% confidence interval [CI], 28% to 42%) compared with 41% (95% CI, 34% to 48%) after UCB and haploidentical transplants, respectively (P = .41). Prespecified analysis of secondary end points recorded higher 2-year nonrelapse mortality after UCB, 18% (95% CI, 13% to 24%), compared with haploidentical transplantation, 11% (95% CI, 6% to 16%), P = .04. This led to lower 2-year overall survival (OS) after UCB compared with haploidentical transplantation, 46% (95% CI, 38-53) and 57% (95% CI 49% to 64%), respectively (P = .04). The trial did not demonstrate a statistically significant difference in the primary end point, 2-year PFS, between the donor sources. Although both donor sources extend access to reduced-intensity transplantation, analyses of secondary end points, including OS, favor haploidentical BM donors. This trial was registered at www.clinicaltrials.gov as #NCT01597778.

    View details for DOI 10.1182/blood.2020007535

    View details for PubMedID 33475736

  • Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma. Blood advances Baird, J. H., Epstein, D. J., Tamaresis, J. S., Ehlinger, Z., Spiegel, J. Y., Craig, J., Claire, G. K., Frank, M. J., Muffly, L., Shiraz, P., Meyer, E., Arai, S., Brown, J. W., Johnston, L., Lowsky, R., Negrin, R. S., Rezvani, A. R., Weng, W. K., Latchford, T., Sahaf, B., Mackall, C. L., Miklos, D. B., Sidana, S. 2021; 5 (1): 143-155

    Abstract

    Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has significantly improved outcomes in the treatment of refractory or relapsed large B-cell lymphoma (LBCL). We evaluated the long-term course of hematologic recovery, immune reconstitution, and infectious complications in 41 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) at a single center. Grade 3+ cytopenias occurred in 97.6% of patients within the first 28 days postinfusion, with most resolved by 6 months. Overall, 63.4% of patients received a red blood cell transfusion, 34.1% of patients received a platelet transfusion, 36.6% of patients received IV immunoglobulin, and 51.2% of patients received growth factor (granulocyte colony-stimulating factor) injections beyond the first 28 days postinfusion. Only 40% of patients had recovered detectable CD19+ B cells by 1 year, and 50% of patients had a CD4+ T-cell count <200 cells per μL by 18 months postinfusion. Patients with durable responses to axi-cel had significantly longer durations of B-cell aplasia, and this duration correlated strongly with the recovery of CD4+ T-cell counts. There were significantly more infections within the first 28 days compared with any other period of follow-up, with the majority being mild-moderate in severity. Receipt of corticosteroids was the only factor that predicted risk of infection in a multivariate analysis (hazard ratio, 3.69; 95% confidence interval, 1.18-16.5). Opportunistic infections due to Pneumocystis jirovecii and varicella-zoster virus occurred up to 18 months postinfusion in patients who prematurely discontinued prophylaxis. These results support the use of comprehensive supportive care, including long-term monitoring and antimicrobial prophylaxis, beyond 12 months after axi-cel treatment.

    View details for DOI 10.1182/bloodadvances.2020002732

    View details for PubMedID 33570626

  • Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma BLOOD ADVANCES Baird, J. H., Epstein, D. J., Tamaresis, J. S., Ehlinger, Z., Spiegel, J. Y., Craig, J., Claire, G. K., Frank, M. J., Muffly, L., Shiraz, P., Meyer, E., Arai, S., Brown, J., Johnston, L., Lowsky, R., Negrin, R. S., Rezvani, A. R., Weng, W., Latchford, T., Sahaf, B., Mackall, C. L., Miklos, D. B., Sidana, S. 2021; 5 (1): 143–55
  • Incidence and Risk Factors Associated with Bleeding and Thrombosis Following Chimeric Antigen Receptor T Cell Therapy. Blood advances Johnsrud, A. J., Craig, J., Baird, J. H., Spiegel, J. Y., Muffly, L., Zehnder, J. L., Tamaresis, J. S., Negrin, R. S., Johnston, L., Arai, S., Shizuru, J. A., Lowsky, R., Meyer, E., Weng, W. K., Shiraz, P., Rezvani, A. R., Latchford, T., Mackall, C. L., Miklos, D. B., Frank, M. J., Sidana, S. 2021

    Abstract

    Bleeding and thrombotic events are an emerging toxicity associated with chimeric antigen receptor (CAR) therapies. To determine their incidence, we retrospectively analyzed consecutive adult patients (n=127) with large B-cell lymphoma (LBCL) or B-cell acute lymphoblastic leukemia (B-ALL) treated between 2017-2020 with axicabtagene ciloleucel (axi-cel) (N=89) or a bispecific CD19/CD22 CAR (N=38). 12 (9.4%) and 8 (6.3%) patients developed bleeding and thrombosis within first 3 months, respectively. In the axi-cel subgroup, these occurred in 11.2% and 6.7%, respectively. Bleeding occurred between days 8-30 (median 17.5), and thrombosis between days 2-91 (median 29). Bleeding sites included genitourinary (N=6), soft tissue (N=2), intracranial (N=2), gastrointestinal (N=1), pulmonary (N=1), and were associated with features of consumptive coagulopathy. On univariate analysis, patients with bleeding were older (median 72 vs. 60 yrs, P<0.01), had lower baseline platelets (86 vs. 178 K/uL, P<0.01), lower platelet nadir after CAR-T (median 17.5 vs. 48 K/uL; P<0.01), lower fibrinogen nadir (median 122 vs. 340 ug/mL; P<0.01) and elevated LDH (P=0.01). ICANS grade ≥3 was associated with increased bleeding (50% vs. 15%; P=0.01), thrombosis (50% vs. 16%; P=0.04), PT prolongation, hypofibrinogenemia and elevated D-dimer. A paucity of events limited multivariate analysis, however low pre-treatment platelets were associated with bleeding in a multivariate logistic regression model. Patients with thrombocytopenia or severe ICANS are at increased risk of bleeding complications and should be closely monitored particularly within the first month after CAR therapy. Future studies in larger cohorts should assess risk factors for systemic coagulopathies in CAR-T therapy, including their association with neurotoxicity.

    View details for DOI 10.1182/bloodadvances.2021004716

    View details for PubMedID 34521106

  • Umbilical cord blood or HLA-haploidentical transplantation: Real world outcomes vs randomized trial outcomes. Transplantation and cellular therapy O'Donnell, P. V., Brunstein, C. G., Fuchs, E. J., Zhang, M. J., Allbee-Johnson, M., Antin, J. H., Leifer, E. S., Elmariah, H., Grunwald, M. R., Hashmi, H., Horowitz, M. M., Magenau, J. M., Majhail, N., Milano, F., Morris, L. E., Rezvani, A. R., McGuirk, J. P., Jones, R. J., Eapen, M. 2021

    Abstract

    Randomized clinical trials offer the highest quality data for modifying clinical practice. Results of a phase III randomized trial of non-myeloablative transplantation for adults with high- risk hematologic malignancies with two umbilical cord blood (UCB) units (n=183) or HLA-haploidentical relative bone marrow (Haplo-BM) (n=154) revealed 2-year progression-free survival (PFS) of 41% and 35% after Haplo-BM and two-unit UCB transplantation, respectively (p=0.41); overall survival was 57% and 46%, respectively (p=0.04), BMT CTN 1101; NCT01597778.We sought to examine the generalizability of BMT CTN 1101 to a contemporaneous cohort beyond the trial's pre-specified 2-year outcomes. All transplantation occurred between June 2012 and June 2018 in the United States. We hypothesized that the results of a rigorous phase III randomized trial will be generalizable. Changes in graft selection for HLA-haploidentical relative transplantation during the trial period allowed comparison of outcomes after transplantation with Haplo-BM to those after haploidentical peripheral blood (Haplo-PB).The trial's broad eligibility criteria were applied to the data source of the Center for International Blood and Marrow Transplant Research to select non-trial subjects. Extended follow up of trial subjects was obtained from this data source. Three separate analyses were performed: 1) trial subjects beyond the trial's 2-year endpoint 2) comparison of trial subjects to a contemporaneous cohort of non-trial subjects (195 two-unit UCB, 358 Haplo-BM, 403 Haplo-PB) and 3) comparison of non-trial subjects by donor and graft type. Multivariate analyses were performed using Cox proportional hazards models for comparison of outcomes by treatment groups.With longer follow up of the trial cohorts, 5-year PFS (37% versus 29%, p=0.08) and overall survival (42% versus 36%, p=0.06) were not significantly different between treatment groups. We then compared the trial results to comparable real-world transplantations. Five-year overall survival after trial and non-trial two-unit UCB (36% versus 41%, p=0.48) and trial and non-trial Haplo-BM (42% versus 47%, p=0.80) transplantation were not different confirming generalizability. The randomized trial did not accrue as planned and therefore lacked the statistical power to detect a 15% difference in progression-free survival. With substantially larger numbers of non-trial Haplo-BM transplantations, 5-year survival was higher after non-trial Haplo-BM compared to trial two-unit UCB (47% versus 36%, p=0.012). Non-trial patients who received Haplo-PB transplantation had higher 5-year survival (54%) compared to trial (HR 0.76, p=0.044) and non-trial (HR 0.78, p=0.026) Haplo-BM. Similarly, survival was higher after Haplo-PB compared to trial (HR 0.57, p<0.0001) and non-trial UCB (HR 0.63, p=0.0002).When considering alternative donor low intensity conditioning regimen transplantation, a haploidentical relative is preferred. Further, PB is the preferred graft.

    View details for DOI 10.1016/j.jtct.2021.11.002

    View details for PubMedID 34775146

  • Outcomes with Autologous or Allogeneic Stem Cell Transplantation in Patients with Plasma Cell Leukemia in the Era of Novel Agents. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Lemieux, C., Johnston, L. J., Lowsky, R., Muffly, L. S., Craig, J. K., Shiraz, P., Rezvani, A., Frank, M. J., Weng, W., Meyer, E., Shizuru, J., Arai, S., Negrin, R., Miklos, D. B., Sidana, S. 2020

    Abstract

    Plasma cell leukemia (PCL) is a rare and very aggressive plasma cell disorder. The optimal treatment approach, including whether to pursue an autologous (autoSCT) or allogeneic (alloSCT) transplant is not clear as there is lack of clinical trial based evidence. This single center retrospective study describes the outcomes of 16 patients with PCL (N=14 primary PCL) who underwent either autoSCT (N=9) or alloSCT (N=7) for PCL in the era of novel agents, between 2007 and 2019. Median age of the cohort was 58 years. High-risk cytogenetics were seen in 50% of patients. All patients received a proteasome inhibitor (PI) and/or immunomodulatory drug (IMiD) based regimen before transplant. At transplant, 10 (62%) patients obtained at least a very good partial response. Response after autoSCT (3 month) was at least VGPR in 6 (67%, CR=5) patients. All patients undergoing alloSCT achieved CR at 3 months. Maintenance was used in 5 patients (56%) after autoSCT. Median PFS from transplant in the autoSCT vs. alloSCT group was 6 vs. 18 months, p=0.09, while median OS from transplant was 19 vs. 40 months (p=0.41), respectively. The median OS from diagnosis was 27 vs. 49 months, p=0.50, respectively. Of all the deaths, 10 (91%) patients died of relapsed disease. In conclusion, alloSCT was not observed to offer any significant survival advantage over autoSCT in PCL, which is comparable to other recent reports and relapse remains the primary cause of death.

    View details for DOI 10.1016/j.bbmt.2020.08.035

    View details for PubMedID 32961371

  • Double unrelated umbilical cord blood versus HLA-haploidentical bone marrow transplantation (BMT CTN 1101). Blood Fuchs, E. J., O'Donnell, P. V., Eapen, M., Logan, B. R., Antin, J. H., Dawson, P., Devine, S. M., Horowitz, M. M., Horwitz, M. E., Karanes, C., Leifer, E., Magenau, J. M., McGuirk, J. P., Morris, L. E., Rezvani, A. R., Jones, R. J., Brunstein, C. G. 2020

    Abstract

    Results of two parallel phase II trials of transplantation of unrelated umbilical cord blood or bone marrow from HLA-haploidentical relatives provided equipoise for direct comparison of these donor sources. Between June 2012 and June 2018, 368 patients aged 18-70 years with chemotherapy-sensitive lymphoma or acute leukemia in remission were randomly assigned to undergo cord blood (n=186) or haploidentical (n=182) transplant. Reduced intensity conditioning comprised total body irradiation with cyclophosphamide and fludarabine for both donor types. Graft-versus-host disease prophylaxis for cord blood transplantation was cyclosporine and mycophenolate mofetil and for haploidentical transplantation, post-transplant cyclophosphamide, tacrolimus and mycophenolate mofetil. The primary endpoint was 2-year progression-free survival. Treatment groups had similar age, sex, self-reported ethnic origin, performance status, disease and disease status at randomization. Two-year progression-free survival was 35% (95% CI, 28-42%) compared to 41% (95% CI, 34-48%) after cord blood and haploidentical transplants, respectively (p=0.41). Pre-specified analysis of secondary endpoints recorded higher 2-year non-relapse mortality after cord blood, 18% (95% CI, 13-24%) compared to haploidentical transplantation, 11% (95% CI, 6-16%), p=0.04. This led to lower 2-year overall survival after cord blood compared to haploidentical transplantation, 46% (95% CI, 38-53) and 57% (95% CI 49-64%), respectively (p=0.04). The trial did not demonstrate a statistically significant difference in the primary endpoint, 2-year progression-free survival, between the donor sources. While both donor sources extend access to reduced intensity transplantation, analyses of secondary endpoints, including overall survival, favor haploidentical bone marrow donors. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute; ClinicalTrials.gov number, NCT01597778).

    View details for DOI 10.1182/blood.2020007535

    View details for PubMedID 32870242

  • Impact of Rituximab and Host/Donor Fc Receptor Polymorphisms after Allogeneic Hematopoietic Cell Transplantation for CD20+ B-cell Malignancies. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Granot, N., Rezvani, A. R., Pender, B. S., Storer, B. E., Sandmaier, B. M., Storb, R., Maloney, D. G. 2020

    Abstract

    We previously reported a 24% 1-year relapse rate in 93 older or medically unfit patients with CD20+ B-cell malignancies after low-intensity conditioning and allogeneic hematopoietic cell transplantation. The current prospective study tested the hypothesis that disease relapse could be reduced, and overall survival improved, by peri-transplant rituximab. Sixty-three patients received rituximab (375 mg/m2/day) on days -3, +10, +24 and +38 in addition to 2-3 Gy total body irradiation ± fludarabine (30 mg/m2 * 3 days). Median rituximab levels of >25 mug/mL were achieved through day +84 after transplant, but levels were not correlated with relapse or graft-vs.-host disease incidence. Recipients with F/F and V/F FCgammaRIIIa polymorphisms showed a trend toward higher relapse rates compared to recipients with V/V polymorphism (p=0.15). No difference in outcome was found with V/V donor pairing. Five-year relapse rates were similar among rituximab-treated patients and historical controls (32% vs, 28%; P=0.94). Rituximab-treated patients experienced higher 5-year overall survival and progression-free survival (47% vs. 38%; P=0.13, 41% vs. 32%; P=0.12, respectively) compared to historical controls transplanted without rituximab, although not statistically significant. Incidences of acute graft-vs.-host disease were similar (Grade II-IV, 57% vs. 56%; Grade III-IV, 13% vs. 17%); and 5-year chronic graft-vs.-host disease incidence was higher among rituximab-treated patients (62% vs. 47%). In patients with relapsed or refractory non-Hodgkin lymphoma, peri-transplant rituximab neither reduced relapse nor improved graft-vs.-host disease. The role of donor-recipient pairing by FCgammaRIIIa polymorphisms in outcome remains to be determined.

    View details for DOI 10.1016/j.bbmt.2020.07.014

    View details for PubMedID 32693210

  • Autologous stem cell transplantation versus no transplant in patients above 70 with multiple myeloma. Lemieux, C., Muffly, L. S., Iberri, D., Rezvani, A., Lowsky, R., Frank, M., Craig, J. K., Liedtke, M., Negrin, R., Weng, W., Meyer, E., Johnston, L. J., Shizuru, J., Shiraz, P., Arai, S., Miklos, D., Sidana, S. LIPPINCOTT WILLIAMS & WILKINS. 2020
  • Impact of proteasome inhibitor vs. IMiD maintenance therapy on outcomes of patients with high-risk multiple myeloma (HRMM). Tam, E., Iberri, D., Liedtke, M., Muffly, L. S., Shiraz, P., Frank, M., Lowsky, R., Rezvani, A., Negrin, R., Meyer, E., Arai, S., Johnston, L. J., Shizuru, J., Weng, W., Miklos, D., Sidana, S. LIPPINCOTT WILLIAMS & WILKINS. 2020
  • Subsequent neoplasms and late mortality in children undergoing allogeneic transplantation for nonmalignant diseases. Blood advances Kahn, J. M., Brazauskas, R., Tecca, H. R., Bo-Subait, S., Buchbinder, D., Battiwala, M., Flowers, M. E., Savani, B. N., Phelan, R., Broglie, L., Abraham, A. A., Keating, A. K., Daly, A., Wirk, B., George, B., Alter, B. P., Ustun, C., Freytes, C. O., Beitinjaneh, A. M., Duncan, C., Copelan, E., Hildebrandt, G. C., Murthy, H. S., Lazarus, H. M., Auletta, J. J., Myers, K. C., Williams, K. M., Page, K. M., Vrooman, L. M., Norkin, M., Byrne, M., Diaz, M. A., Kamani, N., Bhatt, N. S., Rezvani, A., Farhadfar, N., Mehta, P. A., Hematti, P., Shaw, P. J., Kamble, R. T., Schears, R., Olsson, R. F., Hayashi, R. J., Gale, R. P., Mayo, S. J., Chhabra, S., Rotz, S. J., Badawy, S. M., Ganguly, S., Pavletic, S., Nishihori, T., Prestidge, T., Agrawal, V., Hogan, W. J., Inamoto, Y., Shaw, B. E., Satwani, P. 2020; 4 (9): 2084–94

    Abstract

    We examined the risk of subsequent neoplasms (SNs) and late mortality in children and adolescents undergoing allogeneic hematopoietic cell transplantation (HCT) for nonmalignant diseases (NMDs). We included 6028 patients (median age, 6 years; interquartile range, 1-11; range, <1 to 20) from the Center for International Blood and Marrow Transplant Research (1995-2012) registry. Standardized mortality ratios (SMRs) in 2-year survivors and standardized incidence ratios (SIRs) were calculated to compare mortality and SN rates with expected rates in the general population. Median follow-up of survivors was 7.8 years. Diagnoses included severe aplastic anemia (SAA; 24%), Fanconi anemia (FA; 10%), other marrow failure (6%), hemoglobinopathy (15%), immunodeficiency (23%), and metabolic/leukodystrophy syndrome (22%). Ten-year survival was 93% (95% confidence interval [95% CI], 92% to 94%; SMR, 4.2; 95% CI, 3.7-4.8). Seventy-one patients developed SNs (1.2%). Incidence was highest in FA (5.5%), SAA (1.1%), and other marrow failure syndromes (1.7%); for other NMDs, incidence was <1%. Hematologic (27%), oropharyngeal (25%), and skin cancers (13%) were most common. Leukemia risk was highest in the first 5 years posttransplantation; oropharyngeal, skin, liver, and thyroid tumors primarily occurred after 5 years. Despite a low number of SNs, patients had an 11-fold increased SN risk (SIR, 11; 95% CI, 8.9-13.9) compared with the general population. We report excellent long-term survival and low SN incidence in an international cohort of children undergoing HCT for NMDs. The risk of SN development was highest in patients with FA and marrow failure syndromes, highlighting the need for long-term posttransplantation surveillance in this population.

    View details for DOI 10.1182/bloodadvances.2019000839

    View details for PubMedID 32396620

  • Allogeneic Hematopoietic Cell Transplantation for Adult Acute Lymphoblastic Leukemia: Significant Increase in Survival in the Post-Targeted Immunotherapy Era Muffly, L., Arai, S., Johnston, L., Lowsky, R., Meyer, E. H., Miklos, D. B., Negrin, R. S., Rezvani, A., Shiraz, P., Shizuru, J. A., Sidana, S., Weng, W., Cunanan, K. ELSEVIER SCIENCE INC. 2020: S106
  • Prospective Randomized Study of Advance Directives in Allogeneic Hematopoietic Cell Transplant Recipients Muffly, L., Ramirez, Y., Burnash, S., Bisetti, E., Rezvani, A., Sundaram, V. ELSEVIER SCIENCE INC. 2020: S199
  • Autologous tumor cell vaccine induces antitumor T cell immune responses in patients with mantle cell lymphoma: A phase I/II trial. The Journal of experimental medicine Frank, M. J., Khodadoust, M. S., Czerwinski, D. K., Haabeth, O. A., Chu, M. P., Miklos, D. B., Advani, R. H., Alizadeh, A. A., Gupta, N. K., Maeda, L. S., Reddy, S. A., Laport, G. G., Meyer, E. H., Negrin, R. S., Rezvani, A. R., Weng, W. K., Sheehan, K. n., Faham, M. n., Okada, A. n., Moore, A. H., Phillips, D. L., Wapnir, I. L., Brody, J. D., Levy, R. n. 2020; 217 (9)

    Abstract

    Here, we report on the results of a phase I/II trial (NCT00490529) for patients with mantle cell lymphoma who, having achieved remission after immunochemotherapy, were vaccinated with irradiated, CpG-activated tumor cells. Subsequently, vaccine-primed lymphocytes were collected and reinfused after a standard autologous stem cell transplantation (ASCT). The primary endpoint was detection of minimal residual disease (MRD) within 1 yr after ASCT at the previously validated threshold of ≥1 malignant cell per 10,000 leukocyte equivalents. Of 45 evaluable patients, 40 (89%) were found to be MRD negative, and the MRD-positive patients experienced early subsequent relapse. The vaccination induced antitumor CD8 T cell immune responses in 40% of patients, and these were associated with favorable clinical outcomes. Patients with high tumor PD-L1 expression after in vitro exposure to CpG had inferior outcomes. Vaccination with CpG-stimulated autologous tumor cells followed by the adoptive transfer of vaccine-primed lymphocytes after ASCT is feasible and safe.

    View details for DOI 10.1084/jem.20191712

    View details for PubMedID 32558897

  • CD22-Directed CAR T-Cell Therapy Induces Complete Remissions in CD19-Directed CAR-Refractory Large B-Cell Lymphoma. Blood Baird, J. H., Frank, M. J., Craig, J. n., Patel, S. n., Spiegel, J. Y., Sahaf, B. n., Oak, J. S., Younes, S. n., Ozawa, M. n., Yang, E. n., Natkunam, Y. n., Tamaresis, J. S., Ehlinger, Z. n., Reynolds, W. D., Arai, S. n., Johnston, L. n., Lowsky, R. n., Meyer, E. n., Negrin, R. S., Rezvani, A. R., Shiraz, P. n., Sidana, S. n., Weng, W. K., Davis, K. L., Ramakrishna, S. n., Schultz, L. n., Mullins, C. D., Jacob, A. P., Kirsch, I. R., Feldman, S. A., Mackall, C. L., Miklos, D. B., Muffly, L. n. 2020

    Abstract

    The prognosis for patients with large B-cell lymphoma (LBCL) progressing after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first three consecutive patients with autologous CAR19-refractory LBCL treated with a single infusion of autologous 1×106 CAR+ T-cells/kg targeting CD22 (CAR22) as part of a phase I dose escalation study. CAR22 therapy was relatively well tolerated, without any observed non-hematologic adverse events higher than grade 2. Following infusion, all three patients achieved complete remission, with all responses ongoing at the time of last follow up (mean 7.8 months, range 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range 85.4-350 cells/µL), and persisted beyond three months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA (ctDNA) beyond six months post-infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients who have failed prior CAR T-cell therapies. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT04088890).

    View details for DOI 10.1182/blood.2020009432

    View details for PubMedID 33512414

  • Nonmyeloablative allogeneic transplantation achieves clinical and molecular remission in cutaneous T-cell lymphoma. Blood advances Weng, W. K., Arai, S. n., Rezvani, A. n., Johnston, L. n., Lowsky, R. n., Miklos, D. n., Shizuru, J. n., Muffly, L. n., Meyer, E. n., Negrin, R. S., Wang, E. n., Almazan, T. n., Million, L. n., Khodadoust, M. n., Li, S. n., Hoppe, R. T., Kim, Y. H. 2020; 4 (18): 4474–82

    Abstract

    The majority of patients with refractory, advanced-stage mycosis fungoides (MF) or Sézary syndrome (SS) have a life expectancy of <5 years. Here, we report a phase 2 study of a novel nonmyeloablative allogeneic transplantation strategy tailored for this patient population. This study has completed the enrollment, and 35 patients (13 MF, 22 SS) have undergone transplant as planned. The majority (80%) of the patients had stage IV disease and received multiple previous systemic therapies. All patients had active disease at the time of conditioning using total skin electron beam therapy, total lymphoid irradiation, and antithymocyte globulin, and received allograft infusion as outpatients. Cyclosporine or tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis. Patients tolerated the transplant well, with 1- and 2-year nonrelapse mortality of 3% and 14%, respectively. The day +180 cumulative incidence of grade 2 to 4 acute GVHD was 16%, and the 2-year incidence of moderate/severe chronic GVHD was 32%. With a median posttransplant follow-up of 5.4 years, the 2-, 3-, and 5-year overall survival rates were 68%, 62%, and 56%. Using high-throughput sequencing of the T-cell receptor for minimal residual disease monitoring, we observed that 43% achieved molecular remission, which was associated with a lower incidence of disease progression or relapse (9% vs 87%; P = .02). Our study also showed that patients who were aged ≥65 years at the time of allotransplant had similar clinical outcomes compared with younger patients. Thus, we have developed an alternative and potentially curative nonmyeloablative allogeneic transplant regimen for patients with advanced stage MF/SS. This trial was registered at www.clinicaltrials.gov as #NCT00896493.

    View details for DOI 10.1182/bloodadvances.2020001627

    View details for PubMedID 32941647

  • Outcomes with autologous stem cell transplant vs. non-transplant therapy in patients 70 years and older with multiple myeloma. Bone marrow transplantation Lemieux, C. n., Muffly, L. S., Rezvani, A. n., Lowsky, R. n., Iberri, D. J., Craig, J. K., Frank, M. J., Johnston, L. J., Liedtke, M. n., Negrin, R. n., Weng, W. K., Meyer, E. n., Shizuru, J. n., Shiraz, P. n., Arai, S. n., Miklos, D. B., Sidana, S. n. 2020

    Abstract

    We evaluated 79 patients with multiple myeloma (MM) ≥70 years referred to our blood and marrow transplant clinic, within 1 year of diagnosis from 2010 to 2019, for consideration of autologous stem cell transplant (ASCT). Thirty-eight (48%) of 79 patients underwent ASCT. ASCT was not pursued in 41 (52%) patients due to: patient or physician preference in 80% (n = 33) or ineligibility in 20% (n = 8). Baseline characteristics of patients in the two groups were similar. Median PFS from treatment start amongst patients undergoing ASCT (n = 38) vs. not (n = 41) was 41 months vs. 33 months, p = 0.03. There was no difference in OS, with estimated 5-year OS of 73% vs. 83%, respectively (p = 0.86). Day +100 transplant-related mortality (TRM) was 0%. ASCT was an independent favorable prognostic factor for PFS in multivariate analysis, after accounting for HCT-CI score, performance status, hematologic response, and maintenance. Finally, patients ≥70 years undergoing ASCT had similar PFS compared to a contemporaneous institutional cohort of patients <70 years (n = 631) (median PFS from transplant: 36 vs. 47 months, p = 0.25). In this retrospective analysis, ASCT was associated with low TRM and better PFS in fit older adults with MM compared to non-transplant therapy, with comparable benefits as seen in younger patients.

    View details for DOI 10.1038/s41409-020-01026-7

    View details for PubMedID 32782351

  • No Engraftment Advantage after Single or Double Umbilical Cord Blood Transplant (CBT) with the Addition of a Non-HLA Matched Off-the-Shelf Expanded Cord Blood Unit Compared to Conventional CBT: Results of a Randomized Trial Milano, F., Rezvani, A. R., Kurtzberg, J., Karanes, C., Gutman, J. A., Duncan, C., Keyzner, A., Hanna, R., Marmon, T., Dahlberg, A., Delaney, C. AMER SOC HEMATOLOGY. 2019
  • Improved Outcomes for Relapsed/Refractory Classic Hodgkin Lymphoma Following Autologous Stem Cell Transplantation in the Era of Novel Agents Sica, R., Spinner, M. A., Tamaresis, J. S., Advani, R. H., Johnston, L. J., Lowsky, R., Meyer, E. H., Miklos, D. B., Muffly, L. S., Rezvani, A. R., Shizuru, J. A., Weng, W., Negrin, R. S., Arai, S. AMER SOC HEMATOLOGY. 2019
  • Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipients JCI INSIGHT Meyer, E. H., Laport, G., Xie, B. J., MacDonald, K., Heydari, K., Sahaf, B., Tang, S., Baker, J., Armstrong, R., Tate, K., Tadisco, C., Arai, S., Johnston, L., Lowsky, R., Muffly, L., Rezvani, A. R., Shizuru, J., Weng, W., Sheehan, K., Miklos, D., Negrin, R. S. 2019; 4 (10)
  • Daily Dosing of Busulfan in Allogeneic Hematopoietic Cell Transplantation Reduces Costs with Equivalent or Superior Outcomes Singhal, S., Kim, T. Y., Tierney, D., Rezvani, A. ELSEVIER SCIENCE INC. 2019
  • Dose-Intense BCNU/Melphalan Regimen Followed By Autologous Hematopoietic Cell Transplantation (AHCT) Results in Prolonged PFS in Myeloma Patients Gandhi, A., Rezvani, A., Lowsky, R., Johnston, L., Shizuru, J. A., Miklos, D. B., Arai, S., Muffly, L., Meyer, E. H., Negrin, R. S., Weng, W. ELSEVIER SCIENCE INC. 2019
  • Allogeneic hematopoietic cell transplantation provides effective salvage despite refractory disease or failed prior autologous transplant in angioimmunoblastic T-cell lymphoma: a CIBMTR analysis. Journal of hematology & oncology Epperla, N., Ahn, K. W., Litovich, C., Ahmed, S., Battiwalla, M., Cohen, J. B., Dahi, P., Farhadfar, N., Farooq, U., Freytes, C. O., Ghosh, N., Haverkos, B., Herrera, A., Hertzberg, M., Hildebrandt, G., Inwards, D., Kharfan-Dabaja, M. A., Khimani, F., Lazarus, H., Lazaryan, A., Lekakis, L., Murthy, H., Nathan, S., Nishihori, T., Pawarode, A., Prestidge, T., Ramakrishnan, P., Rezvani, A. R., Romee, R., Shah, N. N., Sureda, A., Fenske, T. S., Hamadani, M. 2019; 12 (1): 6

    Abstract

    BACKGROUND: There is a paucity of data on the role of allogeneic hematopoietic cell transplantation (allo-HCT) in patients with angioimmunoblastic T-cell lymphoma (AITL). Using the CIBMTR registry, we report here the outcomes of AITL patients undergoing an allo-HCT.METHODS: We evaluated 249 adult AITL patients who received their first allo-HCT during 2000-2016.RESULTS: The median patient age was 56years (range=21-77). Majority of the patients were Caucasians (86%), with a male predominance (60%). Graft-versus-host disease (GVHD) prophylaxis was predominantly calcineurin inhibitor-based approaches while the most common graft source was peripheral blood (97%). Median follow-up of survivors was 49months (range=4-170months). The cumulative incidence of grade 2-4 and grade 3-4 acute GVHD at day 180 were 36% (95% CI=30-42) and 12 (95% CI=8-17), respectively. The cumulative incidence of chronic GVHD at 1year was 49% (95%CI 43-56). The 1-year non-relapse mortality (NRM) was 19% (95% CI=14-24), while the 4-year relapse/progression, progression-free survival (PFS), and overall survival (OS) were 21% (95% CI=16-27), 49% (95% CI=42-56), and 56% (95% CI=49-63), respectively. On multivariate analysis, chemoresistant status at the time of allo-HCT was associated with a significantly higher risk for therapy failure (inverse of PFS) (RR=1.73 95% CI=1.08-2.77), while KPS <90% was associated with a significantly higher risk of mortality (inverse of OS) (RR=3.46 95% CI=1.75-6.87).CONCLUSION: Our analysis shows that allo-HCT provides durable disease control even in AITL patients who failed a prior auto-HCT and in those subjects with refractory disease at the time of allografting.

    View details for PubMedID 30630534

  • Incidence of Active Tuberculosis Following Hematopoietic Cell Transplantation: A Small but Real Threat. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Aronson, J. R., Rezvani, A. R., Subramanian, A. n. 2019

    View details for DOI 10.1093/cid/ciz592

    View details for PubMedID 31297538

  • Costs and outcomes with once-daily versus every-six-hour intravenous busulfan in allogeneic hematopoietic cell transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation Singhal, S. n., Kim, T. n., Jenkins, P. n., Bassett, B. n., Tierney, D. K., Rezvani, A. R. 2019

    Abstract

    The high cost of healthcare in the United States have not been consistently associated with improved health outcomes or quality of care, necessitating a focus on value-based care. We identified busulfan dosing frequency during allogeneic hematopoietic cell transplantation (HCT) conditioning as a potential target for optimization. To improve patient convenience and to decrease the cost of busulfan-based conditioning regimens, our institution changed busulfan dose frequency from every six-hours (q6h) to once-daily (q24h). We compared costs and patient outcomes between these two dose schedules.In June 2017, our institution transitioned from q6h to q24h busulfan dosing. We compared patients receiving busulfan/cyclophosphamide conditioning regimens (BU/CY) for allogeneic HCT in the year prior to the dosing change (q6h cohort) to those in the year after the dosing change (q24h cohort). The primary outcomes were difference in cost, day +90 mortality, and day +90 relapse.Between June 1, 2016 and June 1, 2018, 104 patients (age 49, 20-63 years) received BU/CY before allogeneic HCT. Fifty-nine patients (57%) received q6h busulfan, and 45 (43%) received q24h busulfan. There were fewer men in the q24h busulfan cohort (42%) compared to the q6h busulfan cohort (64%, p=0.024), but there were no other significant differences between the groups. There was an average cost savings of $19,990 per patient per year with q24h busulfan compared to q6h busulfan, and an annual busulfan cost savings of $899,550.00. There was a significantly lower day +90 mortality in the q24h busulfan cohort compared to the q6h busulfan cohort (0% vs 10%, p=0.028). There were no significant differences in relapse at day +90 or in hospital length of stay.Intravenous busulfan dosing for allogeneic HCT conditioning is a target for improved value-based care. At our institution, patients who received q24h busulfan dosing had similar or superior outcomes compared to those receiving q6h dosing, with a reduction in average cost of $19,990 per patient per year and an overall annual reduction in busulfan costs of approximately $900,000.00. These data support the adoption of q24h intravenous busulfan dosing as a standard of care to improve value-based care in allogeneic HCT.

    View details for DOI 10.1016/j.bbmt.2019.09.008

    View details for PubMedID 31525492

  • Nonmyeloablative TLI-ATG conditioning for allogeneic transplantation: mature follow-up from a large single-center cohort. Blood advances Spinner, M. A., Kennedy, V. E., Tamaresis, J. S., Lavori, P. W., Arai, S. n., Johnston, L. J., Meyer, E. H., Miklos, D. B., Muffly, L. S., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Weng, W. K., Hoppe, R. T., Strober, S. n., Lowsky, R. n. 2019; 3 (16): 2454–64

    Abstract

    Nonmyeloablative total lymphoid irradiation and antithymocyte globulin (TLI-ATG) conditioning is protective against graft-versus-host disease (GVHD), while retaining graft-versus-tumor activity across various hematologic malignancies. We report our comprehensive experience using TLI-ATG conditioning in 612 patients with hematologic malignancies who underwent allogeneic transplantation at Stanford University from 2001 to 2016. All patients received granulocyte colony-stimulating factor-mobilized peripheral blood grafts and cyclosporine and mycophenolate mofetil for GVHD prophylaxis. The median age was 60 years (range, 21-78), with a median follow-up of 6.0 years (range, 1.0-16.4). Common diagnoses included acute myeloid leukemia (AML; n = 193), myelodysplastic syndrome (MDS; n = 94), chronic lymphocytic leukemia (CLL; n = 80), non-Hodgkin lymphoma (NHL; n = 175), and Hodgkin lymphoma (HL; n = 35). Thirty-four percent of patients had a comorbidity index ≥3, 30% had a high to very high disease risk index, and 56% received unrelated donor grafts, including 15% with HLA-mismatched donors. Ninety-eight percent underwent transplant in the outpatient setting, and 57% were never hospitalized from days 0 through 100. The 1-year rates of nonrelapse mortality (NRM), grade II-IV acute GVHD, and extensive chronic GVHD were 9%, 14%, and 22%, respectively. The 4-year estimates for overall and progression-free survival were 42% and 32% for AML, 30% and 21% for MDS, 67% and 43% for CLL, 68% and 45% for NHL, and 78% and 49% for HL. Mixed chimerism correlated with the risk of relapse. TLI-ATG conditioning was well tolerated, with low rates of GVHD and NRM. Durable remissions were observed across hematologic malignancies, with particularly favorable outcomes for heavily pretreated lymphomas. Several efforts are underway to augment donor chimerism and reduce relapse rates while maintaining the favorable safety and tolerability profile of this regimen.

    View details for DOI 10.1182/bloodadvances.2019000297

    View details for PubMedID 31427277

  • Missed diagnosis and misdiagnosis of infectious diseases in hematopoietic cell transplant recipients: an autopsy study. Blood advances Multani, A. n., Allard, L. S., Wangjam, T. n., Sica, R. A., Epstein, D. J., Rezvani, A. R., Ho, D. Y. 2019; 3 (22): 3602–12

    Abstract

    Hematopoietic cell transplantation (HCT) is potentially curative for patients with hematologic disorders, but carries significant risks of infection-related morbidity and mortality. Infectious diseases are the second most common cause of death in HCT recipients, surpassed only by progression of underlying disease. Many infectious diseases are difficult to diagnose and treat, and may only be first identified by autopsy. However, autopsy rates are decreasing despite their value. The clinical and autopsy records of adult HCT recipients at our center who underwent autopsy between 1 January 2000 and 31 December 2017 were reviewed. Discrepancies between premortem clinical diagnoses and postmortem autopsy diagnoses were evaluated. Of 185 patients who underwent autopsy, 35 patients (18.8%) had a total of 41 missed infections. Five patients (2.7%) had >1 missed infection. Of the 41 missed infections, 18 (43.9%) were viral, 16 (39.0%) were fungal, 5 (12.2%) were bacterial, and 2 (4.9%) were parasitic. According to the Goldman criteria, 31 discrepancies (75.6%) were class I, 5 (12.2%) were class II, 1 (2.4%) was class III, and 4 (9.8%) were class IV. Autopsies of HCT recipients frequently identify clinically significant infectious diseases that were not suspected premortem. Had these infections been suspected, a change in management might have improved patient survival in many of these cases. Autopsy is underutilized and should be performed regularly to help improve infection-related morbidity and mortality. Illustrative cases are presented and the lessons learned from them are also discussed.

    View details for DOI 10.1182/bloodadvances.2019000634

    View details for PubMedID 31743391

  • Nonmyeloablative Allogeneic Transplantation Using TLI-ATG Conditioning for Lymphoid and Myeloid Malignancies: Mature Follow-up from a Large, Single Institution Cohort Spinner, M. A., Kennedy, V. E., Tamaresis, J. S., Lavori, P. W., Elder, L. V., Arai, S., Johnston, L. J., Meyer, E. H., Miklos, D. B., Muffly, L. S., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Weng, W., Hoppe, R. T., Strober, S., Lowsky, R. AMER SOC HEMATOLOGY. 2018
  • Elevated Axicabtagene Ciloleucel (CAR-19) Expansion By Immunophenotyping Is Associated with Toxicity in Diffuse Large B-Cell Lymphoma Spiegel, J. Y., Sahaf, B., Hossain, N., Frank, M. J., Claire, G., Abramian, M., Latchford, T., Villa, B., Cancilla, J., Oak, J., Natkunam, Y., Long, S. R., Arai, S., Johnston, L. J., Lowsky, R., Meyer, E. H., Muffly, L. S., Negrin, R. S., Rezvani, A. R., Shizuru, J. A., Weng, W., Kong, K. A., Mackall, C. L., Miklos, D. B. AMER SOC HEMATOLOGY. 2018
  • Autologous Transplantation in Follicular Lymphoma with Early Therapy Failure: A National LymphoCare Study and Center for International Blood and Marrow Transplant Research Analysis BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Casulo, C., Friedberg, J. W., Ahn, K. W., Flowers, C., DiGilio, A., Smith, S. M., Ahmed, S., Inwards, D., Aljurf, M., Chen, A., Choe, H., Cohen, J., Copelan, E., Farooq, U., Fenske, T. S., Freytes, C., Gaballa, S., Ganguly, S., Jethava, Y., Kamble, R. T., Kenkre, V. P., Lazarus, H., Lazaryan, A., Olsson, R. F., Rezvani, A. R., Rizzieri, D., Seo, S., Shah, G. L., Shah, N., Solh, M., Sureda, A., William, B., Cumpston, A., Zelenetz, A. D., Link, B. K., Hamadani, M. 2018; 24 (6): 1163–71

    Abstract

    Patients with follicular lymphoma (FL) experiencing early therapy failure (ETF) within 2 years of frontline chemoimmunotherapy have poor overall survival (OS). We analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) and the National LymphoCare Study (NLCS) to determine whether autologous hematopoietic cell transplant (autoHCT) can improve outcomes in this high-risk FL subgroup. ETF was defined as failure to achieve at least partial response after frontline chemoimmunotherapy or lymphoma progression within 2 years of frontline chemoimmunotherapy. We identified 2 groups: the non-autoHCT cohort (patients from the NLCS with ETF not undergoing autoHCT) and the autoHCT cohort (CIBMTR patients with ETF undergoing autoHCT). All patients received rituximab-based chemotherapy as frontline treatment; 174 non-autoHCT patients and 175 autoHCT patients were identified and analyzed. There was no difference in 5-year OS between the 2 groups (60% versus 67%, respectively; P = .16). A planned subgroup analysis showed that patients with ETF receiving autoHCT soon after treatment failure (≤1 year of ETF; n = 123) had higher 5-year OS than those without autoHCT (73% versus 60%, P = .05). On multivariate analysis, early use of autoHCT was associated with significantly reduced mortality (hazard ratio, .63; 95% confidence interval, .42 to .94; P = .02). Patients with FL experiencing ETF after frontline chemoimmunotherapy lack optimal therapy. We demonstrate improved OS when receiving autoHCT within 1 year of treatment failure. Results from this unique collaboration between the NLCS and CIBMTR support consideration of early consolidation with autoHCT in select FL patients experiencing ETF.

    View details for PubMedID 29242111

  • Outcomes of Medicare-age eligible NHL patients receiving RIC allogeneic transplantation: a CIBMTR analysis BLOOD ADVANCES Shah, N. N., Ahn, K., Litovich, C., Fenske, T. S., Ahmed, S., Battiwalla, M., Bejanyan, N., Dahi, P. B., Bolanos-Meade, J., Chen, A. I., Ciurea, S. O., Bachanova, V., DeFilipp, Z., Epperla, N., Farhadfar, N., Herrera, A. F., Haverkos, B. M., Holmberg, L., Hossain, N. M., Kharfan-Dabaja, M. A., Kenkre, V. P., Lazarus, H. M., Murthy, H. S., Nishihori, T., Rezvani, A. R., D'Souza, A., Savani, B. N., Ulrickson, M. L., Waller, E. K., Sureda, A., Smith, S. M., Hamadani, M. 2018; 2 (8): 933–40

    Abstract

    The application of allogeneic hematopoietic cell transplantation (allo-HCT) in non-Hodgkin lymphoma (NHL) patients ≥65 years in the United States is limited by lack of Medicare coverage for this indication. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we report allo-HCT outcomes of NHL patients aged ≥65 years (older cohort; n = 446) compared with a cohort of younger NHL patients aged 55-64 years (n = 1183). We identified 1629 NHL patients undergoing a first reduced-intensity conditioning (RIC) or nonmyeloablative conditioning allo-HCT from 2008 to 2015 in the United States. Cord blood or haploidentical transplants were excluded. The median age was 68 years (range 65-77) for the older cohort vs 60 years (range 55-64) in the younger cohort. The 4-year adjusted probabilities of nonrelapse mortality (NRM), relapse/progression (R/P), progression-free survival (PFS), and overall survival (OS) of the younger and older groups were 24% vs 30% (P = .03), 41% vs 42% (P = .82), 37% vs 31% (P = .03), and 51% vs 46% (P = .07), respectively. Using multivariate analysis, compared with the younger group, the older cohort was associated with increased NRM, but there was no difference between the 2 cohorts in terms of R/P, PFS, or OS. The most common cause of death was disease relapse in both groups. In NHL patients eligible for allo-HCT, there was no difference in OS between the 2 cohorts. Age alone should not determine allo-HCT eligibility in NHL, and Medicare should expand allo-HCT coverage to older adults.

    View details for PubMedID 29685953

  • Infusion of donor-derived CD8(+) memory T cells for relapse following allogeneic hematopoietic cell transplantation BLOOD ADVANCES Muffly, L., Sheehan, K., Armstrong, R., Jensen, K., Tate, K., Rezvani, A. R., Miklos, D., Arai, S., Shizuru, J., Johnston, L., Meyer, E., Weng, W., Laport, G. G., Negrin, R. S., Strober, S., Lowsky, R. 2018; 2 (6): 681–90

    Abstract

    Murine models showed that CD8+CD44hi memory T (TM) cells could eradicate malignant cells without inducing graft-versus-host disease (GVHD). We evaluated the feasibility and safety of infusing freshly isolated and purified donor-derived phenotypic CD8+ TM cells into adults with disease relapse after allogeneic hematopoietic cell transplantation (HCT). Phenotypic CD8 TM cells were isolated after unmobilized donor apheresis using a tandem immunomagnetic selection strategy of CD45RA depletion followed by CD8+ enrichment. Fifteen patients received CD8+ TM cells at escalating doses (1 × 106, 5 × 106, or 10 × 106 cells per kg). Thirteen received cytoreduction before CD8+ TM cell infusion, and 9 had active disease at the time of infusion. Mean yield and purity of the CD8+ TM infusion were 38.1% and 92.8%, respectively; >90% had CD8+ T effector memory phenotype, cytokine expression, and secretion profile. No adverse infusional events or dose-limiting toxicities occurred; GVHD developed in 1 patient (grade 2 liver). Ten patients (67%) maintained or achieved response (7 complete response, 1 partial response, 2 stable disease) for at least 3 months after infusion; 4 of the responders had active disease at the time of infusion. With a median follow-up from infusion of 328 days (range, 118-1328 days), median event-free survival and overall survival were 4.9 months (95% confidence interval [CI], 1-19.3 months) and 19.6 months (95% CI, 5.6 months to not reached), respectively. Collection and enrichment of phenotypic CD8+ TM cells is feasible, well tolerated, and associated with a low incidence of GVHD when administered as a manipulated infusion of donor lymphocytes in patients who have relapsed after HCT. This trial was registered at www.clinicaltrials.gov as #NCT01523223.

    View details for PubMedID 29572391

  • Viral Isolates in the Cerebrospinal Fluid of Hematopoietic Stem Cell Transplant Recipients, 2007-2015 Andermann, T., Asiimwe, E., Buckley, M., Tkachenko, E., Greene, C., Rezvani, A., Bhatt, A. S. ELSEVIER SCIENCE INC. 2018: S378–S379
  • Phase I/II Trial for Patients with Advanced Hematologic Malignancies Undergoing Myeloablative Allogeneic HCT with a T Cell Depleted Graft with Infusion of Conventional T Cells and Regulatory T Cells Meyer, E., Laport, G. G., Tantsura, I., Tang, S., Sahaf, B., Rangarajan, K., Armstrong, R., Tate, K., Tudisco, C., Sheehan, K., Arai, S., Johnston, L., Muffly, L., Lowsky, R., Rezvani, A., Weng, W., Miklos, D., Negrin, R. S. ELSEVIER SCIENCE INC. 2018: S145
  • Acute Graft-versus-Host Disease NEW ENGLAND JOURNAL OF MEDICINE Rezvani, A. R. 2018; 378 (6): 585–86

    View details for PubMedID 29419277

  • Validation of the Hematopoietic Cell Transplantation-Specific Comorbidity Index in Nonmyeloablative Allogeneic Stem Cell Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Veeraputhiran, M., Yang, L., Sundaram, V., Arai, S., Lowsky, R., Miklos, D., Meyer, E., Muffly, L., Negrin, R., Rezvani, A., Shizuru, J., Weng, W., Johnston, L. 2017; 23 (10): 1744–48

    Abstract

    The Hematopoietic Cell Transplantation (HCT)-Specific Comorbidity Index (HCT-CI) has been extensively studied in myeloablative and reduced-intensity conditioning regimens, with less data available regarding the validity of HCT-CI in nonmyeloablative (NMA) allogeneic transplantation. We conducted a retrospective analysis to evaluate the association between HCT-CI and nonrelapse mortality (NRM) and all-cause mortality (ACM) in patients receiving the total lymphoid irradiation and antithymocyte globulin (TLI/ATG) NMA transplantation preparative regimen. We abstracted demographic and clinical data from consecutive patients, who received allogeneic HCT with the TLI/ATG regimen between January 2008 and September 2014, from the Stanford blood and marrow transplantation database. We conducted univariable and multivariable Cox proportional hazards regression models to evaluate the association between HCT-CI and NRM and ACM. In all, 287 patients were included for analysis. The median age of the patients was 61 (range, 22 to 77) years. The median overall survival was 844 (range, 374 to 1484) days. Most patients had Karnofsky performance score of 90 or above (85%). Fifty-two (18%) patients relapsed within 3 months and 108 (38%) patients relapsed within 1 year, with a median time to relapse of 163 (range, 83 to 366) days. Among the comorbidities in the HCT-CI identified at the time of HCT, reduced pulmonary function was the most common (n = 89), followed by prior history of malignancy (n = 39), psychiatric condition (n = 38), and diabetes (n = 31). Patients with higher HCT-CI scores had higher mortality risks for ACM (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.22 to 3.14 for HCT-CI score 1 or 2 and HR, 1.85; 95% CI, 1.11 to 3.08 for HCT-CI score ≥ 3, compared with 0, respectively). Among individual HCT-CI variables, diabetes (HR, 2.31; 95% CI, 1.79 to 2.89; P = .003) and prior solid tumors (HR, 1.75; 95% CI, 1.02 to 3.00; P = .043) were associated with a higher risk of ACM. Higher HCT-CI scores were significantly associated with higher risk of death. HCT-CI is a valid tool for predicting ACM in NMA TLI/ATG allogeneic HCT.

    View details for PubMedID 28668491

  • Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States BLOOD Muffly, L., Pasquini, M. C., Martens, M., Brazauskas, R., Zhu, X., Adekola, K., Aljurf, M., Ballen, K. K., Bajel, A., Baron, F., Battiwalla, M., Beitinjaneh, A., Cahn, J., Carabasi, M., Chen, Y., Chhabra, S., Ciurea, S., Copelan, E., D'Souza, A., Edwards, J., Foran, J., Freytes, C. O., Fung, H. C., Gale, R., Giralt, S., Hashmi, S. K., Hildebrandt, G. C., Ho, V., Jakubowski, A., Lazarus, H., Luskin, M. R., Martino, R., Maziarz, R., McCarthy, P., Nishihori, T., Olin, R., Olsson, R. F., Pawarode, A., Peres, E., Rezvani, A. R., Rizzieri, D., Savani, B. N., Schouten, H. C., Sabloff, M., Seftel, M., Seo, S., Sorror, M. L., Szer, J., Wirk, B. M., Wood, W. A., Artz, A. 2017; 130 (9): 1156–64

    Abstract

    In this study, we evaluated trends and outcomes of allogeneic hematopoietic cell transplantation (HCT) in adults ≥70 years with hematologic malignancies across the United States. Adults ≥70 years with a hematologic malignancy undergoing first allogeneic HCT in the United States between 2000 and 2013 and reported to the Center for International Blood and Marrow Transplant Research were eligible. Transplant utilization and transplant outcomes, including overall survival (OS), progression-free survival (PFS), and transplant-related mortality (TRM) were studied. One thousand one hundred and six patients ≥70 years underwent HCT across 103 transplant centers. The number and proportion of allografts performed in this population rose markedly over the past decade, accounting for 0.1% of transplants in 2000 to 3.85% (N = 298) in 2013. Acute myeloid leukemia and myelodysplastic syndromes represented the most common disease indications. Two-year OS and PFS significantly improved over time (OS: 26% [95% confidence interval (CI), 21% to 33%] in 2000-2007 to 39% [95% CI, 35% to 42%] in 2008-2013, P < .001; PFS: 22% [16% to 28%] in 2000-2007 to 32% [95% CI, 29% to 36%] in 2008-2013, P = .003). Two-year TRM ranged from 33% to 35% and was unchanged over time (P = .54). Multivariable analysis of OS in the modern era of 2008-2013 revealed higher comorbidity by HCT comorbidity index ≥3 (hazard ratio [HR], 1.27; P = .006), umbilical cord blood graft (HR, 1.97; P = .0002), and myeloablative conditioning (HR, 1.61; P = .0002) as adverse factors. Over the past decade, utilization and survival after allogeneic transplant have increased in patients ≥70 years. Select adults ≥70 years with hematologic malignancies should be considered for transplant.

    View details for PubMedID 28674027

  • Allogeneic transplantation for advanced acute myeloid leukemia: The value of complete remission. Cancer Weisdorf, D. J., Millard, H. R., Horowitz, M. M., Hyare, P. S., Champlin, R., Ho, V., Mielcarek, M., Rezvani, A., Stockerl-Goldstein, K., Khoury, H. J., de Lima, M., Saber, W., Sandmaier, B., Zhang, M. J., Eapen, M. 2017

    Abstract

    Patients with acute myeloid leukemia (AML) without complete remission (CR) or in first relapse (Rel1) can have extended leukemia control and survival after allogeneic hematopoietic cell transplantation (HCT). For patients in Rel1 or primary induction failure (PIF), transplantation versus treatment to achieve a second CR (CR2) and subsequent HCT might yield similar outcomes, but available comparative data are scarce.Survival was analyzed in 4682 HCT recipients according to disease status: PIF (N = 1440), Rel1 (failing ≥1 reinduction; N = 1256), and CR2 (N = 1986).Patient, disease, and transplantation characteristics were similar, except that patients in CR2 more often had performance scores of 90% to 100%, de novo AML, and longer CR1 duration. Adverse cytogenetics were more common in patients who experienced PIF. The 5-year survival rate adjusted for performance score, cytogenetic risk, and donor type for CR2 was 39% (95% confidence interval [CI], 37%-41%) compared with 18% (95% CI, 16%-20%) for HCT in Rel1 and 21% (95% CI, 19%-23%) in PIF (P < .0001).Although survival is superior for patients who undergo HCT in CR2, transplantation for selected patients in Rel1 or PIF may still be valuable. These data can guide decision making about additional salvage therapy versus prompt HCT for patients not in CR, but they also highlight that AML is intrinsically more treatable in patients who have favorable-risk cytogenetics, those with longer CR1 duration, and younger patients with better performance status. Cancer 2017. © 2017 American Cancer Society.

    View details for DOI 10.1002/cncr.30536

    View details for PubMedID 28117884

  • HLA-mismatched unrelated donor transplantation using TLI-ATG conditioning has a low risk of GVHD and potent antitumor activity. Blood advances Spinner, M. A., Fernández-Viña, M. n., Creary, L. E., Quinn, O. n., Elder, L. n., Arai, S. n., Johnston, L. J., Meyer, E. H., Miklos, D. B., Muffly, L. S., Negrin, R. S., Shizuru, J. A., Weng, W. K., Laport, G. G., Strober, S. n., Lowsky, R. n., Rezvani, A. R. 2017; 1 (17): 1347–57

    Abstract

    Many patients lack a fully HLA-matched donor for hematopoietic cell transplantation (HCT), and HLA mismatch is typically associated with inferior outcomes. Total lymphoid irradiation and antithymocyte globulin (TLI-ATG) is a nonmyeloablative conditioning regimen that is protective against graft-versus-host disease (GVHD), and we hypothesized that the protective effect would extend beyond HLA-matched donors. We report outcomes for all consecutively transplanted patients at Stanford University from December 2001 through May 2015 who received TLI-ATG conditioning and HCTs from 8 to 9 out of 10 HLA-mismatched unrelated donors (MMUDs, N = 72) compared with 10 out of 10 HLA-matched unrelated donors (MUDs, N = 193). The median age of the patients was 60 years with a median follow-up of 2 years, and there was a similar distribution of lymphoid and myeloid malignancies in both cohorts. There were no significant differences between MMUD and MUD cohorts in overall survival (46% vs 46% at 5 years, P = .86), disease-free survival (38% vs 28% at 5 years, P = .25), nonrelapse mortality (17% vs 12% at 2 years, P = .34), acute GVHD grades III-IV (6% vs 3% at day +100, P = .61), or chronic GVHD (39% vs 35% at 5 years, P = .49). There was a trend toward less relapse in the MMUD cohort (45% vs 60% at 5 years, hazard ratio: 0.71, P = .094), which was significant for patients with lymphoid malignancies (29% vs 57% at 5 years, hazard ratio: 0.55, P = .044). Achieving full donor chimerism was strongly associated with lower relapse rates. TLI-ATG conditioning may overcome the traditionally poorer outcome associated with HLA-mismatched donors and may be particularly well suited for patients with lymphoid malignancies who lack HLA-matched donors.

    View details for PubMedID 29296777

  • Rituximab-containing reduced-intensity conditioning improves progression-free survival following allogeneic transplantation in B cell non-Hodgkin lymphoma. Journal of hematology & oncology Epperla, N. n., Ahn, K. W., Ahmed, S. n., Jagasia, M. n., DiGilio, A. n., Devine, S. M., Jaglowski, S. n., Kennedy, V. n., Rezvani, A. R., Smith, S. M., Sureda, A. n., Fenske, T. S., Kharfan-Dabaja, M. A., Armand, P. n., Hamadani, M. n. 2017; 10 (1): 117

    Abstract

    In B cell non-Hodgkin lymphoma (B-NHL), rituximab-containing reduced-intensity conditioning regimens (R-RIC) have been shown to provide favorable outcomes in single-arm studies; however, large multicenter studies comparing R-RIC and non-rituximab-containing reduced-intensity conditioning regimens (nonR-RIC) have not been performed. Using the CIBMTR database, we report the outcomes of R-RIC versus nonR-RIC regimens in B-NHL.We evaluated 1401 adult B-NHL patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) who received nonR-RIC (n = 1022) or R-RIC (n = 379) regimens. Graft-versus-host disease (GVHD) prophylaxis was limited to calcineurin inhibitor-based approaches.Median follow-up of survivors in the R-RIC and nonR-RIC groups was 47 and 37 months, respectively. On multivariate analysis, no difference was seen between the R-RIC and nonR-RIC cohorts in terms of acute GVHD grade II-IV (RR = 1.14, 95%CI = 0.83-1.56, p = 0.43) or grade III-IV (RR = 1.16, 95%CI = 0.72-1.89, p = 0.54), chronic GVHD (RR = 1.15, 95%CI = 0.92-1.46, p = 0.22), non-relapse mortality (RR = 0.90; 95%CI = 0.67-1.22; p = 0.51), relapse/progression (RR = 0.79; 95%CI = 0.63-1.01; p = 0.055), and mortality (RR = 0.84, 95%CI = 0.69-1.02, p = 0.08) risk. However, R-RIC was associated with a significantly improved progression-free survival (RR = 0.76; 95%CI 0.62-0.92; p = 0.006). On subgroup analysis, mortality benefit was noted in the R-RIC group patients not receiving busulfan-based RIC (RR = 0.76; 95%CI = 0.60-0.96; p = 0.02) and with the use of a higher cumulative rituximab dose (RR = 0.43; 95%CI = 0.21-0.90; p = 0.02).Our analysis shows that inclusion of rituximab in RIC regimens improves progression-free survival in patients with B cell NHL. These data supports the use of R-RIC in B-NHL patients undergoing allo-HCT.

    View details for PubMedID 28606176

  • Allogeneic Transplants from HLA-Mismatched Unrelated Donors Using Total Lymphoid Irradiation and Antithymocyte Globulin Conditioning Retain a Low Risk of Graft-Versus-Host Disease and Non-Relapse Mortality with at Least As Potent Anti-Tumor Activity As with Matched Unrelated Donors Spinner, M. A., Vina, M., Elder, L., Arai, S., Johnston, L., Meyer, E., Miklos, D., Muffly, L., Negrin, R. S., Shizuru, J., Weng, W., Laport, G. G., Strober, S., Lowsky, R., Rezvani, A. R. AMER SOC HEMATOLOGY. 2016
  • Phase I Study of CD8 Memory T-Cell Donor Lymphocyte Infusion for Relapse of Hematologic Malignancies Following Matched Related Donor Allogeneic Hematopoietic Cell Transplantation Muffly, L. S., Sheehan, K., Armstrong, R., Tate, K., Tudisco, C., Rezvani, A. R., Miklos, D., Arai, S., Shizuru, J., Johnston, L., Meyer, E., Weng, W., Laport, G. G., Negrin, R. S., Strober, S., Lowsky, R. AMER SOC HEMATOLOGY. 2016
  • Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT. Blood Ryan, C. E., Sahaf, B., Logan, A. C., O'Brien, S., Byrd, J. C., Hillmen, P., Brown, J. R., Dyer, M. J., Mato, A. R., Keating, M. J., Jaglowski, S., Clow, F., Rezvani, A. R., Styles, L., Coutre, S. E., Miklos, D. B. 2016

    Abstract

    Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD.

    View details for PubMedID 27802969

  • A new standard for HIV-associated lymphoma. Blood Rezvani, A. R. 2016; 128 (8): 1026-1027

    View details for DOI 10.1182/blood-2016-06-723890

    View details for PubMedID 27563144

  • Validation of the hematopoietic cell transplantation-specific comorbidity index in non-myeloablative allogeneic stem cell transplantation. Veeraputhiran, M., Arai, S., Lowsky, R., Miklos, D., Meyer, E., Muffly, L. S., Negrin, R., Rezvani, A. R., Shizuru, J., Weng, W., Johnston, L. J. AMER SOC CLINICAL ONCOLOGY. 2016
  • Long-term outcomes of high-dose melphalan and carmustine followed by autologous hematopoietic cell transplantation for multiple myeloma. Neppalli, A., Shizuru, J., Johnston, L. J., Muffly, L. S., Weng, W., Negrin, R., Meyer, E., Laport, G., Lowsky, R., Arai, S., Miklos, D., Rezvani, A. R. AMER SOC CLINICAL ONCOLOGY. 2016
  • Long-Term Outcomes of AML Patients Using Total Lymphoid Irradiation with Anti-Thymocyte Globulin Nakasone, H., Miklos, D. B., Meyer, E., Rezvani, A., Muffly, L., Weng, W., Arai, S., Johnston, L., Laport, G. G., Shizuru, J. A., Negrin, R., Strober, S., Lowsky, R. ELSEVIER SCIENCE INC. 2016: S204–S205
  • Immune Characterization of Ibrutinib Therapy Following Allohct That Provides GVL Benefit without Gvhd Sahaf, B., Ryan, C. E., Rezvani, A., Nakasone, H., Otani, J., Coutre, S., Lowsky, R., Negrin, R., Miklos, D. B. ELSEVIER SCIENCE INC. 2016: S412
  • Reduced-intensity transplantation for lymphomas using haploidentical related donors vs HLA-matched unrelated donors BLOOD Kanate, A. S., Mussetti, A., Kharfan-Dabaja, M. A., Ahn, K. W., DiGilio, A., Beitinjaneh, A., Chhabra, S., Fenske, T. S., Freytes, C., Gale, R. P., Ganguly, S., Hertzberg, M., Klyuchnikov, E., Lazarus, H. M., Olsson, R., Perales, M., Rezvani, A., Riches, M., Saad, A., Slavin, S., Smith, S. M., Sureda, A., Yared, J., Ciurea, S., Armand, P., Salit, R., Bolanos-Meade, J., Hamadani, M. 2016; 127 (7): 938-947

    Abstract

    We evaluated 917 adult lymphoma patients who received haploidentical (n = 185) or HLA-matched unrelated donor (URD) transplantation either with (n = 241) or without antithymocyte globulin (ATG; n = 491) following reduced-intensity conditioning regimens. Haploidentical recipients received posttransplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, whereas URD recipients received calcineurin inhibitor-based prophylaxis. Median follow-up of survivors was 3 years. The 100-day cumulative incidence of grade III-IV acute GVHD on univariate analysis was 8%, 12%, and 17% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .44). Corresponding 1-year rates of chronic GVHD on univariate analysis were 13%, 51%, and 33%, respectively (P < .001). On multivariate analysis, grade III-IV acute GVHD was higher in URD without ATG (P = .001), as well as URD with ATG (P = .01), relative to haploidentical transplants. Similarly, relative to haploidentical transplants, risk of chronic GVHD was higher in URD without ATG and URD with ATG (P < .0001). Cumulative incidence of relapse/progression at 3 years was 36%, 28%, and 36% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .07). Corresponding 3-year overall survival (OS) was 60%, 62%, and 50% in the 3 groups, respectively, with multivariate analysis showing no survival difference between URD without ATG (P = .21) or URD with ATG (P = .16), relative to haploidentical transplants. Multivariate analysis showed no difference between the 3 groups in terms of nonrelapse mortality (NRM), relapse/progression, and progression-free survival (PFS). These data suggest that reduced-intensity conditioning haploidentical transplantation with posttransplant cyclophosphamide does not compromise early survival outcomes compared with matched URD transplantation, and is associated with significantly reduced risk of chronic GVHD.

    View details for DOI 10.1182/blood-2015-09-671834

    View details for PubMedID 26670632

  • Microbiota Manipulation With Prebiotics and Probiotics in Patients Undergoing Stem Cell Transplantation CURRENT HEMATOLOGIC MALIGNANCY REPORTS Andermann, T. M., Rezvani, A., Bhatt, A. S. 2016; 11 (1): 19-28

    Abstract

    Hematopoietic stem cell transplantation (HSCT) is a potentially life-saving therapy that often comes at the cost of complications such as graft-versus-host disease and post-transplant infections. With improved technology to understand the ecosystem of microorganisms (viruses, bacteria, fungi, and microeukaryotes) that make up the gut microbiota, there is increasing evidence of the microbiota's contribution to the development of post-transplant complications. Antibiotics have traditionally been the mainstay of microbiota-altering therapies available to physicians. Recently, interest is increasing in the use of prebiotics and probiotics to support the development and sustainability of a healthier microbiota. In this review, we will describe the evidence for the use of prebiotics and probiotics in combating microbiota dysbiosis and explore the ways in which they may be used in future research to potentially improve clinical outcomes and decrease rates of graft-versus-host disease (GVHD) and post-transplant infection.

    View details for DOI 10.1007/s11899-016-0302-9

    View details for Web of Science ID 000372595100004

  • Microbiota Manipulation With Prebiotics and Probiotics in Patients Undergoing Stem Cell Transplantation. Current hematologic malignancy reports Andermann, T. M., Rezvani, A., Bhatt, A. S. 2016

    Abstract

    Hematopoietic stem cell transplantation (HSCT) is a potentially life-saving therapy that often comes at the cost of complications such as graft-versus-host disease and post-transplant infections. With improved technology to understand the ecosystem of microorganisms (viruses, bacteria, fungi, and microeukaryotes) that make up the gut microbiota, there is increasing evidence of the microbiota's contribution to the development of post-transplant complications. Antibiotics have traditionally been the mainstay of microbiota-altering therapies available to physicians. Recently, interest is increasing in the use of prebiotics and probiotics to support the development and sustainability of a healthier microbiota. In this review, we will describe the evidence for the use of prebiotics and probiotics in combating microbiota dysbiosis and explore the ways in which they may be used in future research to potentially improve clinical outcomes and decrease rates of graft-versus-host disease (GVHD) and post-transplant infection.

    View details for DOI 10.1007/s11899-016-0302-9

    View details for PubMedID 26780719

  • Donor-Derived CIK Cell Infusion As Consolidative Therapy after Non-Myeloablative Allogeneic Transplant in Patients with Myeloid Neoplasms Narayan, R., Benjamin, J., Laport, G., Tian, L., Tate, K., Elder, L., Galvez, L., Armstrong, R., Sheehan, K., Lowsky, R., Arai, S., Johnston, L., Miklos, D., Muffly, L. S., Rezvani, A. R., Shizuru, J., Weng, W., Strober, S., Negrin, R., Meyer, E. AMER SOC HEMATOLOGY. 2015
  • Phase I/II Clinical Trial of CpG-Activated Whole Cell Vaccine in Mantle Cell Lymphoma (MCL): Results in Safety and Efficacy from Planned Interim Analysis Chu, M. P., Brody, J., Kohrt, H. E., Frank, M. J., Khodadoust, M., Reddy, S., Advani, R. H., Gupta, N. K., Laport, G., Maeda, L. S., Meyer, E., Miklos, D. B., Negrin, R., Rezvani, A. R., Weng, W., Sheehan, K., Faham, M., Czerwinski, D. K., Okada, A., Levy, R. AMER SOC HEMATOLOGY. 2015
  • Molecular Remission One Year Following Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia Predicts Relapse-Free and Overall Survival: A Multi-Institutional Landmark Analysis Logan, A. C., Herrera, A. F., Ryan, C. E., Rezvani, A. R., Kong, K. A., Faham, M., Alatrash, G., Molldrem, J. J., Sargent, R. L., Alyea, E. P., Ho, V. T., Brown, J. R., Ritz, J., Miklos, D. B. AMER SOC HEMATOLOGY. 2015
  • Long-term sustained disease control in patients with mantle cell lymphoma with or without active disease after treatment with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Cancer Vaughn, J. E., Sorror, M. L., Storer, B. E., Chauncey, T. R., Pulsipher, M. A., Maziarz, R. T., Maris, M. B., Hari, P., Laport, G. G., Franke, G. N., Agura, E. D., Langston, A. A., Rezvani, A. R., Storb, R., Sandmaier, B. M., Maloney, D. G. 2015; 121 (20): 3709-3716

    Abstract

    Previously, early results were reported for allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning with 2 Gy of total body irradiation with or without fludarabine and/or rituximab in 33 patients with mantle cell lymphoma (MCL).This study examined the outcomes of 70 patients with MCL and included extended follow-up (median, 10 years) for the 33 initial patients. Grafts were obtained from human leukocyte antigen (HLA)-matched, related donors (47%), unrelated donors (41%), and HLA antigen-mismatched donors (11%).The 5-year incidence of nonrelapse mortality was 28%. The relapse rate was 26%. The 5-year rates of overall survival (OS) and progression-free survival (PFS) were 55% and 46%, respectively. The 10-year rates of OS and PFS were 44% and 41%, respectively. Eighty percent of surviving patients were off immunosuppression at the last follow-up. The presence of relapsed or refractory disease at the time of HCT predicted a higher rate of relapse (hazard ratio [HR], 2.94; P = .05). Despite this, OS rates at 5 (51% vs 58%) and 10 years (43% vs 45%) were comparable between those with relapsed/refractory disease and those undergoing transplantation with partial or complete remission. A high-risk cytomegalovirus (CMV) status was the only independent predictor of worse OS (HR, 2.32; P = .02). A high-risk CMV status and a low CD3 dose predicted PFS (HR, 2.22; P = .03).Nonmyeloablative allogeneic HCT provides a long-term survival benefit for patients with relapsed MCL, including those with refractory disease or multiple relapses. Cancer 2015;121:3709-3716. © 2015 American Cancer Society.

    View details for DOI 10.1002/cncr.29498

    View details for PubMedID 26207349

  • Allogeneic hematopoietic cell transplantation after failed autologous transplant for lymphoma using TLI and anti-thymocyte globulin conditioning BONE MARROW TRANSPLANTATION Rezvani, A. R., Kanate, A. S., Efron, B., Chhabra, S., Kohrt, H. E., Shizuru, J. A., Laport, G. G., Miklos, D. B., Benjamin, J. E., JOHNSTON, L. J., Arai, S., Weng, W., Negrin, R. S., Strober, S., Lowsky, R. 2015; 50 (10): 1286-1292

    Abstract

    We describe 47 patients with lymphoma and failed prior autologous hematopoietic cell transplantation (HCT) who received TLI-ATG (anti-thymocyte globulin) conditioning followed by allogeneic HCT. Thirty-two patients had non-Hodgkin lymphoma (NHL; diffuse large B-cell lymphoma (n=19), T-cell NHL (n=6), mantle cell lymphoma (n=4) or other B-cell subtypes (n=3)), and 15 had Hodgkin lymphoma. The median follow-up was 4.9 (range, 2.1-11.9) years. The cumulative incidence of grade II-IV acute GvHD at day +100 was 12%, and the cumulative incidence of extensive chronic GvHD at 1 year was 36%. The 3-year cumulative incidences of overall survival (OS), PFS and non-relapse mortality (NRM) were 81%, 44% and 7%, respectively. Fifteen patients died (relapse, n=10; NRM, n=5). Among the 25 patients with relapse after allogeneic HCT, 11 (44%) achieved durable (>1 year) CRs following donor lymphocyte infusion or chemoradiotherapy. The majority of surviving patients (75%; n=24) were able to discontinue all immunosuppression. For patients with relapsed lymphoma after autologous HCT, allogeneic HCT using TLI-ATG conditioning is a well-tolerated, predominantly outpatient therapy with low NRM (7% at 3 years), a low incidence of GvHD, durable disease control and excellent OS (81% at 3 years).

    View details for DOI 10.1038/bmt.2015.149

    View details for PubMedID 26146806

  • Long-term outcomes of patients with persistent indolent b cell malignancies undergoing nonmyeloablative allogeneic transplantation. Biology of blood and marrow transplantation Cassaday, R. D., Storer, B. E., Sorror, M. L., Sandmaier, B. M., Guthrie, K. A., Maloney, D. G., Rajendran, J. G., Pagel, J. M., Flowers, M. E., Green, D. J., Rezvani, A. R., Storb, R. F., Press, O. W., Gopal, A. K. 2015; 21 (2): 281-287

    Abstract

    Relapse is least common in patients with indolent B cell (iB) malignancies (ie, iB non-Hodgkin lymphoma [NHL]) who undergo nonmyeloablative allogeneic transplantation (NMAT) in complete remission (CR). However, for the many patients unable to achieve this state, outcomes are poorly described and methods to improve results are unknown. We sought to describe the long-term follow-up and predictive factors for these poor-risk patients unable to achieve CR before NMAT. We identified and evaluated patients with iB-NHL including chronic lymphocytic leukemia treated with fludarabine/total body irradiation-based NMAT that had evidence of persistent disease before NMAT. From December 1998 to April 2009, 89 patients were identified, most commonly with small/chronic lymphocytic lymphoma (n = 62) and follicular lymphoma (n = 24). Pretransplant anti-CD20 radioimmunotherapy (RIT) using standard yttrium-90-ibritumomab tiuxetan was administered to 18 patients (20%) who more frequently had chemoresistant disease (81% versus 39%, P = .003), disease bulk > 5 cm (61% versus 15%, P < .001), thrombocytopenia < 25k/μL (33% versus 7%, P = .002), and Hematopoietic Cell Transplant Comorbidity Index scores ≥ 3 (72% versus 37%, P = .006). After adjusting for these imbalances, RIT-treated patients had improved rates of progression-free survival (PFS) (hazard ratio [HR] = .4; 95% confidence interval [CI], .2 to .9, P = .02) and overall survival (OS) (HR = .3; 95% CI, .1 to .8, P = .008) compared with the non-RIT group. The 3-year adjusted estimates of PFS and OS for the RIT and non-RIT groups were 71% and 87% versus 44% and 59%, respectively. The use of RIT was the only factor independently associated with improved PFS and OS. Rates of nonrelapse mortality and graft-versus-host disease (GVHD) were similar between the 2 groups, although over 70% of patients developed clinically significant acute or chronic GVHD. In conclusion, despite relatively high rates of GVHD, patients with persistent iB-NHL can derive durable benefit from NMAT.

    View details for DOI 10.1016/j.bbmt.2014.10.024

    View details for PubMedID 25445025

  • Long-Term Outcomes of Patients with Advanced Mantle Cell Lymphoma Treated with Allogeneic Hematopoietic Cell Transplantation after Nonmyeloablative Conditioning Vaughn, J., Sorror, M. L., Chauncey, T., Pulsipher, M. A., Maziarz, R. T., Maris, M. B., Hari, P. N., Laport, G. G., Franke, G., Agura, E., Langston, A., Rezvani, A., Stor, R. E., Sandmaier, B. M., Maloney, D. G. ELSEVIER SCIENCE INC. 2015: S88–S89
  • Ibrutinib Treatment of Relapsed CLL Following Allogeneic Transplantation: Sustained Disease Response and Promising Donor Immune Modulation Ryan, C. E., Logan, A. C., Rezvani, A., Kamdar, M., Nakasone, H., Sahaf, B., Otani, J., Kong, K. A., Klinger, M., Faham, M., Coutre, S., Miklos, D. B. ELSEVIER SCIENCE INC. 2015: S307–S308
  • Impact of donor age on outcome after allogeneic hematopoietic cell transplantation. Biology of blood and marrow transplantation Rezvani, A. R., Storer, B. E., Guthrie, K. A., Schoch, H. G., Maloney, D. G., Sandmaier, B. M., Storb, R. 2015; 21 (1): 105-112

    Abstract

    As older patients are eligible for allogeneic hematopoietic cell transplantation (HCT), older siblings are increasingly proposed as donors. We studied the impact of donor age on the tempo of hematopoietic engraftment and donor chimerism, acute and chronic graft-versus-host disease (GVHD), and nonrelapse mortality (NRM) among 1174 consecutive patients undergoing myeloablative and 367 patients undergoing nonmyeloablative HCT from HLA-matched related or unrelated donors with granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell allografts. Sustained engraftment rates were 97% and 98% in patients undergoing myeloablative and nonmyeloablative conditioning, respectively, for grafts from donors < 60 years old (younger; n = 1416) and 98% and 100%, respectively, for those from donors ≥60 years old (older; n = 125). No significant differences were seen in the tempo of neutrophil and platelet recoveries and donor chimerism except for an average 1.3-day delay in neutrophil recovery among myeloablative patients with older donors (P = .04). CD34(+) cell dose had an independent effect on the tempo of engraftment. Aged stem cells did not convey an increased risk of donor-derived clonal disorders after HCT. Myeloablative and nonmyeloablative recipients with older sibling donors had significantly less grade II to IV acute GVHD than recipients with grafts from younger unrelated donors. Rates of grade III and IV acute GVHD, chronic GVHD, and NRM for recipients with older donors were not significantly different from recipients with younger donors. In conclusion, grafts from donors ≥60 years old do not adversely affect outcomes of allogeneic HCT compared with grafts from younger donors.

    View details for DOI 10.1016/j.bbmt.2014.09.021

    View details for PubMedID 25278458

  • Ibrutinib Treatment of Relapsed CLL Following Allogeneic Transplantation: Sustained Disease Response and Promising Donor Immune Modulation Ryan, C. E., Logan, A. C., Rezvani, A., Kamdar, M., Nakasone, H., Sahaf, B., Otani, J., Kong, K. A., Klinger, M., Faham, M., Coutre, S., Miklos, D. B. AMER SOC HEMATOLOGY. 2014
  • Allogeneic hematopoietic cell transplantation for indolent non-Hodgkin lymphoma: indications and outcomes CURRENT OPINION IN HEMATOLOGY Rezvani, A. R., Sandmaier, B. M. 2013; 20 (6): 509-514

    Abstract

    Allogeneic hematopoietic cell transplantation (HCT) can potentially cure indolent non-Hodgkin lymphoma (NHL). However, the optimal timing and indications remain unclear. Here, we review recent published reports on the subject and summarize our approach.Recent prospective clinical trials of allogeneic HCT in indolent NHL are marked by substantial variation in eligibility criteria, patient populations, and transplant approach. Nonetheless, several common themes are apparent. Indolent NHL is highly susceptible to immunologic graft-versus-lymphoma effects and relapse rates after allogeneic HCT are uniformly low. Allogeneic HCT early in the disease course produces the highest overall and progression-free survival, but also increases patient exposure to potential transplant-related complications such as chronic graft-versus-host disease. In contrast, allogeneic HCT can be reserved as a 'last resort' for patients who are refractory to conventional chemotherapy, delaying their exposure to graft-versus-host disease and other transplant-associated risks. No trials have directly addressed the optimal timing of allogeneic HCT in indolent NHL nor prospectively compared different transplant approaches.Excellent outcomes have been reported with allogeneic HCT for indolent NHL, both early and late in the disease course. The optimal timing of allogeneic HCT is unknown and depends heavily on patient preferences.

    View details for DOI 10.1097/MOH.0b013e328365a151

    View details for Web of Science ID 000326746100004

    View details for PubMedID 24104411

  • Inducible costimulator (ICOS) up-regulation on activated T cells in chronic graft-versus-host disease after dog leukocyte antigen-nonidentical hematopoietic cell transplantation: a potential therapeutic target. Transplantation Sato, M., Storb, R., Loretz, C., Stone, D., Mielcarek, M., Sale, G. E., Rezvani, A. R., Graves, S. S. 2013; 96 (1): 34-41

    Abstract

    Inducible costimulator (ICOS), a member of the CD28 family of costimulatory molecules, is induced on CD4 and CD8 T cells after their activation. ICOS functions as an essential immune regulator and ICOS blockade is a potential approach to immune modulation in allogeneic transplantation. Here, we describe the expression profile of ICOS in dogs and determine whether ICOS expression is up-regulated during chronic graft-versus-host disease (GVHD) and host-versus-graft reactions in the canine hematopoietic cell transplantation model.Monoclonal antibodies (mAbs) against cell surface-expressed ICOS were produced and tested in vitro for suppression of canine mixed leukocyte reactions (MLR). Expression of ICOS on CD3 cells was evaluated by flow cytometry using peripheral blood, lymph nodes, and splenocytes obtained from dogs undergoing graft-versus-host and host-versus-graft reactions.Canine ICOS was expressed in an inducible pattern on T cells activated by concanavalin A, anti-CD3 mAb in combination with anti-CD28 mAb, and alloantigen stimulation. Immunosuppressive effects of ICOS blockade were observed in MLR using peripheral blood mononuclear cells from dog leukocyte antigen-nonidentical dogs. Immunosuppressive effects of ICOS blockade were observed in MLR when anti-ICOS was combined with suboptimal concentrations of cytotoxic T-lymphocyte antigen 4-Ig or cyclosporine. ICOS expression was significantly up-regulated on T cells in dogs undergoing graft rejection or chronic GVHD after allogeneic hematopoietic cell transplantation.These studies suggest that ICOS plays a role in graft rejection and GVHD in an outbred animal model, and ICOS blockade may be an approach to prevention and treatment of chronic GVHD.

    View details for DOI 10.1097/TP.0b013e318295c025

    View details for PubMedID 23694952

  • Cyclophosphamide followed by Intravenous Targeted Busulfan for Allogeneic Hematopoietic Cell Transplantation: Pharmacokinetics and Clinical Outcomes BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Rezvani, A. R., McCune, J. S., Storer, B. E., Batchelder, A., Kida, A., Deeg, H. J., McDonald, G. B. 2013; 19 (7): 1033-1039

    Abstract

    Targeted busulfan ((T)BU) and cyclophosphamide (CY) for allogeneic hematopoietic cell transplantation carries a high risk of sinusoidal obstruction syndrome (SOS) in patients undergoing transplantation for myelofibrosis. We tested the hypothesis that reversing the sequence of administration (from (T)BU/CY to CY/(T)BU) would reduce SOS and day +100 nonrelapse mortality. We enrolled 51 patients with myelofibrosis (n = 20), acute myelogenous leukemia (n = 20), or myelodysplastic syndrome (n = 11) in a prospective trial of CY/(T)BU conditioning for allogeneic hematopoietic cell transplantation. CY 60 mg/kg/day i.v. for 2 days was followed by daily i.v. BU for 4 days, targeted to a concentration at steady state (Css) of 800-900 ng/mL. Compared with (T)BU/CY-conditioned patients, CY/(T)BU-conditioned patients had greater exposure to CY (P < .0001) and less exposure to 4-hydroxycyclophosphamide (P < .0001). Clinical outcomes were compared between cases and controls (n = 271) conditioned with (T)BU/CY for the same indications. In patients with myelofibrosis, CY/(T)BU conditioning was associated with a significantly reduced incidence of SOS (0% versus 30% after (T)BU/CY; P = .006), whereas the incidence of SOS was low in both cohorts with acute myelogenous leukemia/myelodysplastic syndrome. Day +100 mortality was significantly lower in the CY/(T)BU cohort (2% versus 13%; P = .01). CY/(T)BU conditioning had a marked affect on the pharmacokinetics of CY and was associated with significantly lower incidence of SOS and day +100 mortality, suggesting that CY/(T)BU is superior to (T)BU/CY as conditioning for patients with myelofibrosis.

    View details for DOI 10.1016/j.bbmt.2013.04.005

    View details for Web of Science ID 000321093500008

    View details for PubMedID 23583825

  • Prevention of graft-vs.-host disease EXPERT OPINION ON PHARMACOTHERAPY Rezvani, A. R., Storb, R. F. 2012; 13 (12): 1737-1750

    Abstract

    Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for many malignant and non-malignant hematologic disorders. However, graft-vs.-host disease (GVHD) remains a major complication of allogeneic HCT and limits the success of this approach.This paper reviews recent developments in the prevention of acute and chronic GVHD. In the setting of acute GVHD prevention, recent trials of T-cell depletion using Fresenius-ATG are reviewed, as well as studies testing total lymphoid irradiation, mesenchymal stromal cells, rituximab, statins, sirolimus and other investigational agents. In the setting of chronic GVHD, results with Fresenius-ATG are reviewed, as well as B-cell depletion with rituximab, and the potential role of the B-cell regulatory cytokine BAFF in chronic GVHD is also discussed. Finally, the emerging role of resident skin and gut bacterial flora-the so-called microbiome-in the pathogenesis of GVHD is covered.Current methods of acute GVHD prevention are highly successful, and a number of investigational approaches promise to further reduce the risk of this complication. By contrast, chronic GVHD is more poorly understood and more difficult to prevent. Future studies are required to delineate the roles of these approaches and to abrogate GVHD without sacrificing the beneficial immunologic graft-vs.-tumor effect.

    View details for DOI 10.1517/14656566.2012.703652

    View details for Web of Science ID 000306524600007

    View details for PubMedID 22770714

  • The Dynamic International Prognostic Scoring System for myelofibrosis predicts outcomes after hematopoietic cell transplantation BLOOD Scott, B. L., Gooley, T. A., Sorror, M. L., Rezvani, A. R., Linenberger, M. L., Grim, J., Sandmaier, B. M., Myerson, D., Chauncey, T. R., Storb, R., Buxhofer-Ausch, V., Radich, J. P., Appelbaum, F. R., Deeg, H. J. 2012; 119 (11): 2657-2664

    Abstract

    Studies by the International Working Group showed that the prognosis of myelofibrosis patients is predicted by the Dynamic International Prognostic Scoring System (DIPSS) risk categorization, which includes patient age, constitutional symptoms, hemoglobin, leukocyte count, and circulating blasts. We evaluated the prognostic usefulness of the DIPSS in 170 patients with myelofibrosis, 12 to 78 years of age (median, 51.5 years of age), who received hematopoietic cell transplantation (HCT) between 1990 and 2009 from related (n = 86) or unrelated donors (n = 84). By DIPSS, 21 patients had low-risk disease, 48 had intermediate-1, 50 had intermediate-2, and 51 had high-risk disease. Five-year incidence of relapse, relapse-free survival, overall survival, and nonrelapse mortality for all patients were 10%, 57%, 57%, and 34%, respectively. Among patients with DIPSS high-risk disease, the hazard ratio for post-HCT mortality was 4.11 (95% CI, 1.44-11.78; P = .008), and for nonrelapse mortality was 3.41 (95% CI, 1.15-10.09; P = .03) compared with low-risk patients. After a median follow-up of 5.9 years, the median survivals have not been reached for DIPSS risk groups low and intermediate-1, and were 7 and 2.5 years for intermediate-2 and high-risk patients, respectively. Thus, HCT was curative for a large proportion of patients with myelofibrosis, and post-HCT success was dependent on pre-HCT DIPSS classification.

    View details for DOI 10.1182/blood-2011-08-372904

    View details for Web of Science ID 000301941700035

    View details for PubMedID 22234678

  • Accurate Targeting of Daily Intravenous Busulfan with 8-Hour Blood Sampling in Hospitalized Adult Hematopoietic Cell Transplant Recipients BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Yeh, R. F., Pawlikowski, M. A., Blough, D. K., McDonald, G. B., O'Donnell, P. V., Rezvani, A., Deeg, H. J., McCune, J. S. 2012; 18 (2): 265-272

    Abstract

    Daily intravenous (i.v.) busulfan is increasingly being used in hematopoietic cell transplantation (HCT) conditioning regimens. Intravenous busulfan doses administered at the traditional frequency of every 6 hours can be targeted ((T)Bu) to a patient-specific concentration at steady state (C(ss)) using therapeutic drug monitoring (TDM). In this report, we describe our experiences with TDM of daily i.v. busulfan in an adult population, with the specific aims of (1) evaluating covariates associated with busulfan clearance, and (2) assessing the feasibility of TDM for outpatient administration of daily (T)Bu with pharmacokinetic sampling over 6 hours. A retrospective pharmacokinetic analysis was conducted in 87 adults receiving daily (T)Bu as part of cyclophosphamide followed by (T)BU (CY/(T)BU), fludarabine monophosphate (fludarabine) followed by (T)BU, or (T)BU concurrent with fludarabine conditioning. The desired C(ss) was achieved in 85% of patients receiving daily i.v. busulfan. Busulfan clearance was not associated with sex or age, but was associated with the day of dosing and conditioning regimen (P = .0016). In patients receiving CY/(T)BU, no differences in clearance were found between dosing days (P > .36); however, clearance decreased significantly in patients receiving fludarabine-based regimens (P = .0016). Busulfan clearance and C(ss) estimates from pharmacokinetic sampling over 8, 11, or 24 hours were comparable (P > .4). However, pharmacokinetic modeling of individual patient concentration-time data over 6 hours could not reliably estimate busulfan clearance or C(ss).

    View details for DOI 10.1016/j.bbmt.2011.06.013

    View details for Web of Science ID 000299398500015

    View details for PubMedID 21736869

  • Decreased Serum Albumin as a Biomarker for Severe Acute Graft-versus-Host Disease after Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Rezvani, A. R., Storer, B. E., Storb, R. F., Mielcarek, M., Maloney, D. G., Sandmaier, B. M., Martin, P. J., McDonald, G. B. 2011; 17 (11): 1594-1601

    Abstract

    Biomarkers capable of predicting the onset and severity of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (HCT) would enable preemptive and risk-stratified therapy. Severe aGVHD leads to gastrointestinal protein loss, resulting in hypoalbuminemia. We hypothesized that decreases in serum albumin at onset of aGVHD would predict the risk of progression to severe aGVHD. We identified 401 patients who developed aGVHD grades II-IV after reduced-intensity allogeneic HCT and reviewed all available serum albumin values from 30 days before HCT to 45 days after initiation of treatment for aGVHD. A ≥0.5 g/dL decrease in serum albumin concentration from pretransplantation baseline to the onset of treatment for aGVHD predicted the subsequent development of grade III/IV aGVHD (versus grade II aGVHD) with a sensitivity of 69% and a specificity of 73%. Overall mortality at 6 months after initiation of aGVHD treatment was 36% versus 17% for patients with and without ≥0.5 g/dL decreases in serum albumin, respectively (P = .0009). We conclude that change in serum albumin concentration from baseline to initiation of aGVHD treatment is an inexpensive, readily available, and predictive biomarker of GVHD severity and mortality after reduced-intensity allogeneic HCT.

    View details for DOI 10.1016/j.bbmt.2011.07.021

    View details for Web of Science ID 000296829000006

    View details for PubMedID 21806949

  • Rituximab resistance BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY Rezvani, A. R., Maloney, D. G. 2011; 24 (2): 203-216

    Abstract

    Rituximab has become a ubiquitous component of treatment regimens for follicular non-Hodgkin lymphoma. Despite widespread clinical use, the mechanisms by which tumor cells resist rituximab-mediated destruction remain unclear. Rituximab relies in part on immune effector mechanisms for its antitumor effect, and thus resistance may be mediated not only by intrinsic tumor-cell alterations but also by the host immunological environment. In this article, we explore the mechanisms of action of rituximab, the incidence of rituximab resistance, and potential mechanisms of resistance. Finally, we discuss novel approaches to modulate the antibody, the tumor cell, and the host immunologic environment to overcome rituximab resistance. Further research into the mechanisms of rituximab resistance will be essential to improving the efficacy of anti-CD20 therapy in NHL, and may also pay dividends in the optimization of monoclonal antibody therapy across a wide range of diseases.

    View details for DOI 10.1016/j.beha.2011.02.009

    View details for Web of Science ID 000292355200010

    View details for PubMedID 21658619

  • Outcomes Following Relapse of Non-Hodgkin Lymphoma (NHL) or Chronic Lymphocytic Leukemia (CLL) After Nonmyeloablative Conditioning and Allogeneic Hematopoietic Cell Transplantation (HCT) From HLA-Matched Related or Unrelated Donors. Sorror, M. L., Storer, B., Sandmaier, B. M., Franke, G. N., Laport, G. G., Chauncey, T., Agura, E., Maris, M. T., Wade, J., Pulsipher, M. A., Maziarz, R. T., Sahebi, F., McSweeney, P., Bruno, B., Vindelov, L., Yeager, A. M., Rezvani, A., Niederwieser, D. W., Blume, K. G., Storb, R. F., Maloney, D. G. AMER SOC HEMATOLOGY. 2010: 553
  • Allogeneic hematopoietic cell transplantation: the state of the art EXPERT REVIEW OF HEMATOLOGY Gyurkocza, B., Rezvani, A., Storb, R. F. 2010; 3 (3): 285-299

    Abstract

    Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative procedure for a variety of hematologic malignancies. The field has evolved substantially over the past decade, with advances in patient and donor selection, stem cell sources, supportive care, prevention of complications and reduced-toxicity preparative regimens. As a result, the indications for HCT and the pool of eligible patients have expanded significantly. In this article, we provide an overview of the major aspects of allogeneic HCT, and focus specifically on areas of active research and on novel approaches to challenges in the field. Specifically, we will discuss approaches to reduce the toxicity of the preparative regimen, with the goal of increasing the safety and applicability of HCT. The availability of suitable donors may be an obstacle to wider application of HCT. We review three major approaches to broadening the donor pool: the use of HLA-mismatched unrelated donors, umbilical cord blood and HLA-haploidentical family donors. Graft-versus-host disease remains a major cause of morbidity and mortality after HCT. We review recent advances in the understanding of this phenomenon, and novel prophylactic and therapeutic approaches that hold the promise of further improving the safety of the procedure. We conclude with a speculative outline of the next 5 years of research in the field of HCT.

    View details for DOI 10.1586/EHM.10.21

    View details for Web of Science ID 000284801600012

    View details for PubMedID 20871781

  • Treatment Change as a Predictor of Outcome among Patients with Classic Chronic Graft-versus-Host Disease BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION Flowers, M. E., Storer, B., Carpenter, P., Rezvoni, A. R., Vigorito, A. C., Campregher, P. V., Moravec, C., Kiem, H., Fero, M., Georges, G., Warren, E., Lee, S., Sanders, J. E., Appelbaum, F., Martin, P. J. 2008; 14 (12): 1380-1384

    Abstract

    We analyzed outcomes for 668 patients who had systemic treatment for chronic graft-versus-host disease (cGVHD) to assess the utility of early treatment change for exacerbation of cGVHD as a surrogate for survival endpoints in clinical trials. Fifty-six percent of patients had treatment change within 2 years after diagnosis of cGVHD. The median onset of treatment change was 4.4 months (range: 0.3-50 months). The cumulative incidence of nonrelapse mortality (NRM) at 2 years was 16%, and overall survival (OS) at 2 years was 74%. In time-dependent Cox models, treatment change was associated with an increase in risk of NRM (hazard ratio, 2.53; 95% confidence interval, 1.7-3.7; P < .0001). The hazard ratio was attenuated by 6% per month of delay in treatment change. Our results confirm that exacerbation of cGVHD is associated with an increased risk of NRM and with decreased OS, but the strength of this association is not large enough to allow the use of early exacerbation as a surrogate for survival endpoints in clinical trials. Other measures of clinical benefit, such as response, will need to be developed as endpoints in phase II trials for patients with cGVHD.

    View details for DOI 10.1016/j.bbmt.2008.09.017

    View details for Web of Science ID 000261754600008

    View details for PubMedID 19041060

  • Separation of graft-vs.-tumor effects from graft-vs.-host disease in allogeneic hematopoietic cell transplantation Center of Excellence Meeting Rezvani, A. R., Storb, R. F. ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD. 2008: 172–79

    Abstract

    Allogeneic hematopoietic cell transplantation (HCT) is an increasingly widely used treatment modality in hematological malignancies. Alloreactivity mediated by donor T cells (and, in some settings, by donor natural killer cells) can produce durable immunologic control or eradication of residual malignancy after allogeneic HCT. However, graft-vs.-tumor (GVT) effects are variably effective and are often accompanied by deleterious alloreactivity against normal host tissue, manifesting as graft-vs.-host disease (GVHD). A major focus of current research in HCT is the separation of beneficial GVT effects from GVHD. Here we review a number of approaches currently under investigation to specifically augment GVT effects, including the identification of minor histocompatibility antigens (mHA), adoptive immunotherapy with tumor-specific or mHA-specific cytotoxic T lymphocytes, vaccination of the donor or recipient to stimulate tumor-specific immunity, and adoptive transfer of natural killer cells. In addition, we review strategies being investigated to specifically suppress GVHD while sparing GVT, including the manipulation and infusion of regulatory T cells, the use of novel pharmacologic and biologic agents, and the use of mesenchymal stem cells. Ultimately, advances in separation of GVT from GVHD will further enhance the potential of allogeneic HCT as a curative treatment for hematological malignancies.

    View details for DOI 10.1016/j.jaut.2007.12.002

    View details for Web of Science ID 000253769900010

    View details for PubMedID 18242060

  • Using allogeneic stem cell/T-cell grafts to cure hematologic malignancies EXPERT OPINION ON BIOLOGICAL THERAPY Rezvani, A. R., Storb, R. 2008; 8 (2): 161-179

    Abstract

    Background: Allogeneic stem cell and T-cell-based therapies are widely used in the treatment of hematologic malignancies and can treat or cure otherwise refractory disease. However, in spite of major advances in the understanding and practice of allogeneic hematopoietic cell transplantation (HCT), several important challenges remain. Objective: Here the authors review the use of allogeneic HCT and T-cell-based therapy, with the goal of providing an overview of the uses and limitations of this approach as well as a survey of areas of active research. Methods: The authors review and summarize recent publications and expert opinions in the field of allogeneic HCT, along with a brief historical perspective, with a focus on challenges and recent advances in the field. Results/conclusion: Present areas of research include efforts to expand the donor pool through the use of umbilical cord blood and human leukocyte antigen-haploidentical donors, the use of reduced-intensity conditioning regimens, which allow treatment of previously ineligible patients, enhancement of immune reconstitution after transplantation, more effective prevention and treatment of acute and chronic graft-versus-host disease, and the augmentation of the immunologic graft-versus-tumor response and its uncoupling from deleterious graft-versus-host alloreactivity.

    View details for DOI 10.1517/14712598.8.2.161

    View details for Web of Science ID 000252878300004

    View details for PubMedID 18194073

  • Outcomes of allogeneic hematopoietic cell transplantation (HCT) after non-myeloablative conditioning in relapsed diffuse large B-cell lymphoma (DLBCL) 49th Annual Meeting of the American-Society-of-Hematology Rezvani, A. R., Norasetthada, L., Gooley, T., Sorror, M., Forman, S. J., Agura, E., Chauncey, T., Maziarz, R. T., Maris, M., Shizuru, J., Bruno, B., Wade, J. C., Lange, T., Yeager, A., Sandmaier, B. M., Storb, R. F., Maloney, D. G. AMER SOC HEMATOLOGY. 2007: 892A–892A